Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof

ABSTRACT

The present invention provides pyrazole derivatives represented by the general formula:  
                 
 
wherein R 1  represents H, an optionally substituted C 1-6  alkyl group etc.; one of Q and T represents a group represented by the general formula:  
                 
 
or a group represented by the general formula:  
                 
 
while the other represents an optionally substituted C 1-6  alkyl group etc.; R 2  represents H, a halogen atom, OH, an optionally substituted C 1-6  alkyl group etc.; X represents a single bond, O or S; Y represents an optionally substituted C 1-6  alkylene group etc.; Z represents —R B , —COR C  etc. in which R B  represents an optionally substituted C 1-6  alkyl group etc.; and R C  represents an optionally substituted C 1-6  alkyl group etc.; R 4  represents H, an optionally substituted C 1-6  alkyl group etc.; and R 3 , R 5  and R 6  represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase of blood galactose level such as galactosemia, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.

TECHNICAL FIELD

The present invention relates to pyrazole derivatives, pharmaceuticallyacceptable salts thereof or prodrugs thereof which are useful asmedicaments, pharmaceutical compositions comprising the same,pharmaceutical uses thereof and intermediates for production thereof.

More particularly, the present invention relates to pyrazole derivativeshaving an inhibitory activity in human SGLT1, pharmaceuticallyacceptable salts thereof or prodrugs thereof which are useful as agentsfor the prevention or treatment of a disease associated withhyperglycemia such as diabetes, impaired glucose tolerance, impairedfasting glycemia, diabetic complications or obesity, and a diseaseassociated with the increase of blood galactose level such asgalactosemia, pharmaceutical compositions comprising the same,pharmaceutical uses thereof and intermediates for production thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. In addition, it has beenconfirmed by large-scale clinical trial that it is necessary to practicea long-term control of blood sugar level strictly so as to preventpatients with diabetes from occuring and advancing diabeticcomplications by recieving treatment (see the following References 1 and2). Furthermore, many epidemiologic studies on impaired glucosetolerance and macroangiopathy show that impaired glucose tolerance asthe boundary type is also a risk factor in macroangiopathy as well asdiabetes. Thus, needs to improve postprandial hyperglycemia have beenfocused (see the following Reference 3).

In recent years, development of various antidiabetic agents has beenprogressing with the background of a rapid increase of patients withdiabetes. For example, α-glucosidase inhibitors, which delaycarbohydrate digestion and absorption at the small intestine, are usedto improve postprandial hyperglycemia. It has been also reported thatacarbose, one of α-glucosidase inhibitors, has an effect of preventingor delaying the incidence of diabetes by applying to patients withimpaired glucose tolerance (see the following Reference 4). However,since α-glucosidase inhibitors do not affect elevated glucose levels byingesting a monosaccharide of glucose (see the following Reference 5),with recently changing compositions of sugars in meals, it has beendesired to develop agents which exert a wider range of activitiesinhibiting carbohydrate absorption.

In the meantime, it has been known that SGLT1, sodium-dependent glucosetransporter 1, exists in the small intestine which controls carbohydrateabsorption. It has been also reported that insufficiency of glucose andgalactose absorption arises in patients with dysfunction due tocongenital abnormalities of human SGLT1 (seethe following References6-8). In addition, it has been confirmed that SGLT1 is involved inglucose and galactose absorption (see the following References 9 and10).

Furthermore, it is confirmed that mRNA and protein of SGLT1 increase andabsorption of glucoses are accelerated in OLETF rats and rats withstreptozotocin-induced diabetic symptoms (see the following References11 and 12). Generally in patients with diabetes, carbohydrate digestionand absorption are increased. For example, it is confirmed that mRNA andprotein of SGLT1 are highly increased in the human small intestine (seethe following Reference 13).

Therefore, blocking a human SGLT1 activity inhibits absorption ofcarbohydrates such as glucose at the small intestine, subsequently canprevent increase of blood sugar level. Especially, it is considered thatdelaying glucose absorption based on the above mentioned mechanism iseffective to normalize postprandial hyperglycemia. In addition, sinceincrease of SGLT1 in the small intestine is thought to contribute toincreased carbohydrate absorption, fast development of agents, whichhave a potent inhibitory activity in human SGLT1, has been desired forthe prevention or treatment of diabetes.

-   Reference 1: The Diabetes Control and Complications Trial Research    Group, N. Engl. J. Med., 1993.9, Vol. 329, No. 14, pp. 977-986;-   Reference 2: UK Prospective Diabetes StudyGroup, Lancet, 1998.9,    Vol. 352, No. 9131, pp. 837-853;-   Reference 3: Makoto, TOMINAGA, Endocrinology & Diabetology, 2001.11,    Vol. 13, No. 5, pp. 534-542;-   Reference 4: Jean-Louis Chiasson and 5 persons, Lancet, 2002.6, Vol.    359, No. 9323, pp. 2072-2077;-   Reference 5: Hiroyuki, ODAKA and 3 persons, Journal of Japanese    Society of Nutrition and Food Science, 1992, Vol. 45, No. 1, pp.    27-31;-   Reference 6: Tadao, BABA and 1 person, Supplementary volume of    Nippon Rinsho, Ryoikibetsu Shokogun, 1998, No. 19, pp. 552-554;-   Reference 7: Michihiro, KASAHARA and 2 persons, Saishin Igaku,    1996.1, Vol. 51, No. 1, pp. 84-90;-   Reference 8: Tomofusa, TSUCHIYA and 1 person, Nippon Rinsho, 1997.8,    Vol. 55, No. 8, pp. 2131-2139;-   Reference 9: Yoshikatsu, KANAI, Kidney and Dialysis, 1998.12, Vol.    45, extra edition, pp. 232-237;-   Reference 10: E. Turk and 4 persons, Nature, 1991.3, Vol. 350, pp.    354-356;-   Reference 11: Y. Fujita and 5 persons, Diabetologia, 1998, Vol. 41,    pp. 1459-1466;-   Reference 12: J. Dyer and 5 persons, Biochemical Society    Transactions, 1997, Vol. 25, p. 479S;-   Reference 13: J. Dyer and 4 persons, American Journal of Physiology,    2002.2, Vol. 282, No. 2, pp. G241-G248

DISCLOSURE OF THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT1. As a result, it was found thatcertain pyrazole derivatives represented by the following generalformula (I) show an inhibitory activity in human SGLT1 at the smallintestine and exert an excellent inhibitory activity in increase ofblood glucose level as shown below, thereby forming the basis of thepresent invention.

The present invention is to provide novel pyrazole derivatives whichexert an excellent inhibitory activity of blood glucose level increaseby showing an inhibitory activity in human SGLT1 and inhibitingabsorption of carbohydrate such as glucose at the small intestine,pharmaceutically acceptable salts thereof or prodrugs thereof, and toprovide pharmaceutical compositions comprising the same, pharmaceuticaluses thereof and intermediates for production thereof.

This is, the present invention relates to

-   -   [1] a pyrazole derivative represented by the general formula:        wherein    -   R¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆        alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl        group, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl        group which may have the same or different 1 to 3 substituents        selected from the group consisting of a halogen atom, a hydroxy        group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, or an aryl(C₁₋₆ alkyl) group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring;    -   one of Q and T represents a group represented by the formula:        or a group represented by the formula:    -   while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆        alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a        C₃₋₇ cycloalkyl group;    -   R² represents a hydrogen atom, a halogen atom, a hydroxy group,        a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group,        a halo(C₁₋₆ alkyl) group, a halo(C₁₋₆ alkoxy) group, a C₁₋₆        alkoxy-substituted (C₁₋₆ alkoxy) group, a C₃₋₇        cycloalkyl-substituted (C₂₋₆ alkoxy) group or -A-R^(A) in which        A represents a single bond, an oxygen atom, a methylene group,        an ethylene group, —OCH₂— or —CH₂O—; and R^(A) represents a C₃₋₇        cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group        which may have the same or different 1 to 3 substituents        selected from the group consisting of a halogen atom, a hydroxy        group, an amino group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group,        a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a        hydroxy(C₁₋₆ alkyl) group, a carboxy group, a C₂₋₇        alkoxycarbonyl group, a cyano group and a nitro group, or a        heteroaryl group which may have a substituent selected from the        group consisting of a halogen atom and a C₁₋₆ alkyl group;    -   X represents a single bond, an oxygen atom or a sulfur atom;    -   Y represents a C₁₋₆ alkylene group which may be substituted by a        hydroxy group or a C₂₋₆ alkenylene group;    -   Z represents —R^(B), —COR^(C), —SO₂R^(C), —CON(R^(D))R^(E),        —SO₂NHR^(F) or —C(═NR^(G))N(R^(H))R^(I);    -   R^(C) represents an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group, an amino group, a C₁₋₆        alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, a heteroaryl group which may have a substituent selected        from the group consisting of a halogen atom, an amino group and        a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the        same or different 1 to 5 groups selected from the following        substituent group (i);    -   R⁴, R^(B), R^(D), R^(E) and R^(F) are the same or different, and        each represents a hydrogen atom, an aryl group which may have        the same or different 1 to 3 substituents selected from the        group consisting of a halogen atom, a hydroxy group, an amino        group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a        C₁₋₆ alkoxy group, a heteroaryl group which may have a        substituent selected from the group consisting of a halogen        atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl        group which may have the same or different 1 to 5 groups        selected from the following substituent group (i), or both of R⁴        and R^(B) bind together with the neighboring nitrogen atom to        form a C₂₋₆ cyclic amino group which may have a substituent        selected from the group consisting of a hydroxy group, a        carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, or both        of R^(D) and R^(E) bind together with the neighboring nitrogen        atom to form a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group;    -   R^(G), R^(H) and R^(I) are the same or different, and each        represents a hydrogen atom, a cyano group, a carbamoyl group, a        C₂₋₇ acyl group, a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇        alkoxycarbonyl) group, a nitro group, a C₁₋₆ alkylsulfonyl        group, a sulfamide group, a carbamimidoyl group, or a C₁₋₆ alkyl        group which may have the same or different 1 to 5 groups        selected from the following substituent group (i), or both of        R^(G) and R^(H) bind to form an ethylene group, or both of R^(H)        and R^(I) bind together with the neighboring nitrogen atom to        form a C₂₋₆ cyclic amino group which may have a substituent        selected from the group consisting of a hydroxy group, a        carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group;    -   R³, R⁵ and R⁶ are the same or different, and each represents a        hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆        alkoxy group; and    -   substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy        group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆        alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,        an ureido group, a sulfamide group, a mono or di(C₁₋₆        alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a        C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆        alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl        group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or        different, and each represents a hydrogen atom or a C₁₋₆ alkyl        group which may have the same or different 1 to 3 substituents        selected from the group consisting of a hydroxy group, an amino        group, a mono or di(C₁₋₆ alkyl)amino group, a mono or        di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or        di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆        alkylsulfonylamino group and a carbamoyl group, or both of R^(J)        and R^(K) bind together with the neighboring nitrogen atom to        form a C₂₋₆ cyclic amino group which may have a substituent        selected from the group consisting of a hydroxy group, a        carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an        aryl(C₁₋₆ alkoxy) group which may have the same or different 1        to 3 substituents selected from the group consisting of a        halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆        alkylthio) group which may have the same or different 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a        C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆        heterocycloalkyl group, an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group, an amino group, a C₁₋₆        alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, a heteroaryl group which may have a substituent selected        from the group consisting of a halogen atom, an amino group and        a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl (C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a        C₁₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl        group as a substituent,        or a pharmaceutically acceptable salt thereof;    -   [2] a pyrazole derivative described in the above [1] wherein R⁴        represents a hydrogen atom, an aryl group which may have the        same or different 1 to 3 substituents selected from the group        consisting of a halogen atom, a hydroxy group, an amino group, a        C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆        alkoxy group, a heteroaryl group which may have a substituent        selected from the group consisting of a halogen atom, an amino        group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may        have the same or different 1 to 5 groups selected from the        following substituent group (i); R^(B) represents an aryl group        which may have the same or different 1 to 3 substituents        selected from the group consisting of a halogen atom, a hydroxy        group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆        alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which        may have a substituent selected from the group consisting of a        halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆        alkyl group which may have the same or different 1 to 5 groups        selected from the following substituent group (i); R^(C)        represents an aryl group which has the same or different 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino        group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl        group which may have a substituent selected from the group        consisting of a halogen atom, an amino group and a C₁₋₆ alkyl        group, or a C₁₋₆ alkyl group which has the same or different 1        to 5 groups selected from the following substituent group (i);        and    -   substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy        group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆        alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,        an ureido group, a sulfamide group, a mono or di(C₁₋₆        alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a        C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆        alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl        group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or        different, and each represents a hydrogen atom or a C₁₋₆ alkyl        group which may have the same or different 1 to 3 substituents        selected from the group consisting of a hydroxy group, an amino        group, a mono or di(C₁₋₆ alkyl)amino group, a mono or        di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or        di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆        alkylsulfonylamino group and a carbamoyl group, or both of R^(J)        and R^(K) bind together with the neighboring nitrogen atom to        form a C₂₋₆ cyclic amino group which may have a substituent        selected from the group consisting of a hydroxy group, a        carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an        aryl(C₁₋₁₆ alkoxy) group which may have the same or different 1        to 3 substituents selected from the group consisting of a        halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆        alkylthio) group which may have the same or different 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a        C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆        heterocycloalkyl group, an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group, an amino group, a C₁₋₆        alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, a heteroaryl group which may have a substituent selected        from the group consisting of a halogen atom, an amino group and        a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl (C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a        C₁₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl        group as a substituent,        or a pharmaceutically acceptable salt thereof;    -   [3] a pyrazole derivative described in the above [2] wherein Z        represents —R^(B); R^(B) represents an aryl group which has the        same or different 1 to 3 substituents selected from the group        consisting of a halogen atom, a hydroxy group, an amino group, a        C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆        alkoxy group, a heteroaryl group which may have a substituent        selected from the group consisting of a halogen atom, an amino        group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which has        the same or different 1 to 5 groups selected from the following        substituent group (i); and    -   substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy        group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆        alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group,        an ureido group, a sulfamide group, a mono or di(C₁₋₆        alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a        C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆        alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl        group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or        different, and each represents a hydrogen atom or a C₁₋₆ alkyl        group which may have the same or different 1 to 3 substituents        selected from the group consisting of a hydroxy group, an amino        group, a mono or di(C₁₋₆ alkyl)amino group, a mono or        di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or        di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆        alkylsulfonylamino group and a carbamoyl group, or both of R^(J)        and R^(K) bind together with the neighboring nitrogen atom to        form a C₂₋₆ cyclic amino group which may have a substituent        selected from the group consisting of a hydroxy group, a        carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an        aryl(C₁₋₆ alkoxy) group which may have the same or different 1        to 3 substituents selected from the group consisting of a        halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆        alkylthio) group which may have the same or different 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a        C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆        heterocycloalkyl group, an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group, an amino group, a C₁₋₆        alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, a heteroaryl group which may have a substituent selected        from the group consisting of a halogen atom, an amino group and        a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a        carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a        C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a        C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl        group as a substituent,        or a pharmaceutically acceptable salt thereof;    -   [4] a pyrazole derivative described in the above [3] wherein R⁴        represents a hydrogen atom; R^(B) represents a C₁₋₆ alkyl group        which has the same or different 1 to 5 groups selected from the        following substituent group (iA); and    -   substituent group (iA) consists of a hydroxy group, an amino        group, a mono or di (C₁₋₆ alkyl) amino group, a carboxy group, a        C₂₋₇ alkoxycarbonyl group and —CON(R^(JA))R^(KA) in which R^(JA)        and R^(KA) are the same or different, and each represents a        hydrogen atom or a C₁₋₆ alkyl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a hydroxy group, an amino group, a mono or di(C₁₋₆        alkyl)amino group and a carbamoyl group, or both of R^(JA) and        R^(KA) bind together with the neighboring nitrogen atom to form        a C₂₋₆ cyclic amino group which may have a substituent selected        from the group consisting of a C₁₋₆ alkyl group and a        hydroxy(C₁₋₆ alkyl) group,        or a pharmaceutically acceptable salt thereof;    -   [5] a pyrazole derivative described in the above [4] wherein        R^(B) represents a C₁₋₆ alkyl group which has a carbamoyl group,        or a pharmaceutically acceptable salt thereof;    -   [6] a pyrazole derivative described in the above [2] wherein Z        represents —CON(R^(D))R^(E), or a pharmaceutically acceptable        salt thereof;    -   [7] a pyrazole derivative described in the above [6] wherein        R^(D) represents a hydrogen atom; R^(E) represents a C₁₋₆ alkyl        group which has the same or different 1 to 5 groups selected        from the following substituent group (iB); and substituent group        (iB) consists of a hydroxy group, an amino group, a mono or        di(C₁₋₆ alkyl)amino group and —CON(R^(JB))R^(KB) in which R^(JB)        and R^(KB) are the same or different, and each represents a        hydrogen atom, a C₁₋₆ alkyl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a hydroxy group, an amino group and a mono or di(C₁₋₆        alkyl)amino group, or pharmaceutically acceptable salt thereof;    -   [8] a pyrazole derivative described in the above [2] wherein Z        represents —C(═NR^(G) G)N(R^(H))R^(I), or pharmaceutically        acceptable salt thereof;    -   [9] a pyrazole derivative described in the above [8] wherein        R^(G) represents a hydrogen atom or a C₁₋₆ alkylsulfonyl group;        R^(H) represents a hydrogen atom; R^(I) represents a hydrogen        atom or a C₁₋₆ alkyl group which may have the same or different        1 to 5 groups selected from the following substituent group        (iC); and substituent group (iC) consists of a hydroxy group, an        amino group, a mono or di(C₁₋₆ alkyl)amino group, or        pharmaceutically acceptable salt thereof;    -   [10] a pyrazole derivative described in the above [2] wherein Z        represents —COR^(C); R^(C) represents a C₁₋₆ alkyl group which        has a group selected from the following substituent group (iD);        and substituent group (iD) consists of an amino group and        —CON(R^(JC))R^(KC) in which both of R^(JC) and R^(KC) bind        together with the neighboring nitrogen atom to form a C₂₋₆        cyclic amino group which may have a substituent selected from        the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆        alkyl) group, or pharmaceutically acceptable salt thereof;    -   [11] a pyrazole derivative described in any one of the above        [1]-[10] wherein X represents a single bond or an oxygen atom;        and Y represents an ethylene group or a trimethylene group,        or pharmaceutically acceptable salt thereof;    -   [12] a pyrazole derivative described in any one of the above        [1]-[11] wherein R¹ represents a hydrogen atom or a hydroxy(C₂₋₆        alkyl) group; T represents a group represented by the formula:        or a group represented by the formula:        Q represents a C₁₋₆ alkyl group or a halo(C₁₋₆ alkyl) group; and        R³, R⁵ and R⁶ represent a hydrogen atom, or a pharmaceutically        acceptable salt thereof;    -   [13] a pyrazole derivative described in any one of the above        [1]-[11] wherein one of Q and T represents a group represented        by the formula:        the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl)        group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇        cycloalkyl group, or a pharmaceutically acceptable salt thereof;    -   [14] a pyrazole derivative described in the above [12] or [13]        wherein T represents a group represented by the formula:        or a pharmaceutically acceptable salt thereof;    -   [15] a pyrazole derivative described in the above [12] or [14]        wherein Q represents an isopropyl group, or a pharmaceutically        acceptable salt thereof;    -   [16] a prodrug of a pyrazole derivative described in any one of        the above [1]-[15] or a pharmaceutically acceptable salt        thereof;    -   [17] a prodrug described in the above [16] wherein T represents        a group represented by the formula:        or a group represented by the formula:        in which the hydroxy group at the 4-position is substituted by a        glucopyranosyl group or a galactopyranosyl group, or the hydroxy        group at the 6-position is substituted by a glucopyranosyl        group, a galactopyranosyl group, a C₂₋₇ acyl group, a C₁₋₆        alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇        alkoxycarbonyl-substituted (C₂₋₇ acyl) group, a C₂₋₇        alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group or a        C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group;    -   [18] a pyrazole derivative described in the above [1] which is a        compound selected from the group consisting of compounds        described in the following Example numbers and pharmaceutically        acceptable salts thereof,

-   Example 28, Example 29, Example 32, Example 33, Example 45, Example    48, Example 51, Example 52 (Example 111), Example 55, Example 56,    Example 57, Example 59, Example 66, Example 67, Example 71, Example    77, Example 79, Example 81, Example 82, Example 83, Example 84,    Example 87, Example 90, Example 94, Example 107, Example 108,    Example 109, Example 114, Example 117, Example 118, Example 119,    Example 121, Example 123, Example 124, Example 126, Example 127,    Example 128, Example 129, Example 130, Example 134, Example 141,    Example 147, Example 150, Example 151, Example 170, Example 175,    Example 177, Example 178, Example 179, Example 180 and Example 181;    -   [19] a pharmaceutical composition comprising as an active        ingredient a pyrazole derivative described in any one of the        above [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof;    -   [20] a human SGLT1 inhibitor comprising as an active ingredient        a pyrazole derivative described in any one of the above        [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof;    -   [21] an agent for inhibiting postprandial hyperglycemia        comprising as an active ingredient a pyrazole derivative        described in any one of the above [1]-[18], a pharmaceutically        acceptable salt thereof or a prodrug thereof;    -   [22] an agent for the prevention or treatment of a disease        associated with hyperglycemia, which comprises as an active        ingredient a pyrazole derivative described in any one of the        above [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof;    -   [23] an agent for the prevention or treatment described in the        above [22] wherein the disease associated with hyperglycemia is        a disease selected from the group consisting of diabetes,        impaired glucose tolerance, impaired fasting glycemia, diabetic        complications, obesity, hyperinsulinemia, hyperlipidemia,        hypercholesterolemia, hypertriglyceridemia, lipid metabolism        disorder, atherosclerosis, hypertension, congestive heart        failure, edema, hyperuricemia and gout;    -   [24] an agent for the inhibition of advancing impaired glucose        tolerance or impaired fasting glycemia into diabetes in a        subject, which comprises as an active ingredient a pyrazole        derivative described in any one of the above [1]-[18], a        pharmaceutically acceptable salt thereof or a prodrug thereof;    -   [25] an agent for the prevention or treatment of a disease        associated with the increase of blood galactose level, which        comprises as an active ingredient a pyrazole derivative        described in any one of the above [1]-[18], a pharmaceutically        acceptable salt thereof or a prodrug thereof;    -   [26] an agent for the prevention or treatment described in the        above [25] wherein the disease associated with the increase of        blood galactose level is galactosemia;    -   [27] a pharmaceutical composition described in the above [19]        wherein the dosage form is sustained release formulation;    -   [28] an agent described in any one of the above [20]-[26]        wherein the dosage form is sustained release formulation;    -   [29] a method for the prevention or treatment of a disease        associated with hyperglycemia, which comprises administering an        effective amount of a pyrazole derivative described in any one        of the above [1]-[18], a pharmaceutically acceptable salt        thereof or a prodrug thereof;    -   [30] a method for the inhibition of advancing impaired glucose        tolerance or impaired fasting glycemia into diabetes in a        subject, which comprises administering an effective amount of a        pyrazole derivative described in anyone of the above [1-[18], a        pharmaceutically acceptable salt thereof or a prodrug thereof;    -   [31] a method for the prevention or treatment of a disease        associated with the increase of blood galactose level, which        comprises administering an effective amount of a pyrazole        derivative described in any one of the above [1]-[18], a        pharmaceutically acceptable salt thereof or a prodrug thereof;    -   [32] a use of a pyrazole derivative described in any one of the        above [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof for the manufacture of a pharmaceutical        composition for the prevention or treatment of a disease        associated with hyperglycemia;    -   [33] a use of a pyrazole derivative described in any one of the        above [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof for the manufacture of a pharmaceutical        composition for the inhibition of advancing impaired glucose        tolerance or impaired fasting glycemia into diabetes in a        subject;    -   [34] a use of a pyrazole derivative described in any one of the        above [1]-[18], a pharmaceutically acceptable salt thereof or a        prodrug thereof for the manufacture of a pharmaceutical        composition for the prevention or treatment of a disease        associated with the increase of blood galactose level;    -   [35] a pharmaceutical combination which comprises (A) a pyrazole        derivative described in any one of the above [1]-[18], a        pharmaceutically acceptable salt thereof or a prodrug thereof,        and (B) at least one member selected from the group consisting        of an insulin sensitivity enhancer, a glucose absorption        inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2        inhibitor, an insulin or insulin analogue, a glucagon receptor        antagonist, an insulin receptor kinase stimulant, a tripeptidyl        peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a        protein tyrosine phosphatase-1B inhibitor, a glycogen        phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a        fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase        inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol,        a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1,        a glucagon-like peptide-1 analogue, a glucagon-like peptide-1        agonist, amylin, an amylin analogue, an amylin agonist, an        aldose reductase inhibitor, an advanced glycation endproducts        formation inhibitor, a protein kinase C inhibitor, a        γ-aminobutyric acid receptor antagonist, a sodium channel        antagonist, a transcript factor NF-κB inhibitor, a lipid        peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase        inhibitor, insulin-like growth factor-I, platelet-derived growth        factor, a platelet-derived growth factor analogue, epidermal        growth factor, nerve growth factor, a carnitine derivative,        uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol,        sulodexide, Y-128, antidiarrhoics, cathartics, a        hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric        acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A        cholesterol acyltransferase inhibitor, probcol, a thyroid        hormone receptor agonist, a cholesterol absorption inhibitor, a        lipase inhibitor, a microsomal triglyceride transfer protein        inhibitor, a lipoxygenase inhibitor, a carnitine        palmitoyl-transferase inhibitor, a squalene synthase inhibitor,        a low-density lipoprotein receptor enhancer, a nicotinic acid        derivative, a bile acid sequestrant, a sodium/bile acid        cotransporter inhibitor, a cholesterol ester transfer protein        inhibitor, an appetite suppressant, an angiotensin-converting        enzyme inhibitor, a neutral endopeptidase inhibitor, an        angiotensin II receptor antagonist, an endothelin-converting        enzyme inhibitor, an endothelin receptor antagonist, a diuretic        agent, a calcium antagonist, a vasodilating antihypertensive        agent, a sympathetic blocking agent, a centrally acting        antihypertensive agent, an α₂-adrenoceptor agonist, an        antiplatelets agent, a uric acid synthesis inhibitor, a        uricosuric agent and a urinary alkalinizer;    -   [36] a method for the prevention or treatment of a disease        associated with hyperglycemia or a disease associated with the        increase of blood galactose level, which comprises administering        an effective amount of a drug selected from the above group (A)        and at least one member selected from the above group (B);    -   [37] a method for the inhibition of advancing impaired glucose        tolerance or impaired fasting glycemia into diabetes in a        subject, which comprises administering an effective amount of a        drug selected from the above group (A) and at least one member        selected from the above group (B);    -   [38] a use of a drug selected from the above group (A) and at        least one member selected from the above group (B) for the        manufacture of a pharmaceutical composition for the prevention        or treatment of a disease associated with hyperglycemia or a        disease associated with the increase of blood galactose level;    -   [39] a use of a drug selected from the above group (A) and at        least one member selected from the above group (B) for the        manufacture of a pharmaceutical composition for the inhibition        of advancing impaired glucose tolerance or impaired fasting        glycemia into diabetes in a subject;    -   [40] a pyrazole derivative represented by the general formula:        wherein    -   R¹¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆        alkenyl group, a hydroxy(C₂₋₆ alkyl) group which may have a        protective group, a C₃₋₇ cycloalkyl group, a C₃₋₇        cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl group which        may have the same or different 1 to 3 substituents selected from        the group consisting of a halogen atom, a hydroxy group which        may have a protective group, an amino group which may have a        protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or        an aryl(C₁₋₆ alkyl) group which may have the same or different 1        to 3 substituents selected from the group consisting of a        halogen atom, a hydroxy group which may have a protective group,        an amino group which may have a protective group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring;    -   one of Q² and T² represents a        2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group, a        2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy group, a        2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy group or a        2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyloxy group, while        the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl)        group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇        cycloalkyl group;    -   R¹² represents a hydrogen atom, a halogen atom, a hydroxy group        which may have a protective group, a C₁₋₆ alkyl group, a C₁₋₆        alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆ alkyl) group,        a halo(C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy-substituted (CL-6        alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group        or -A-R^(1A) in which A represents a single bond, an oxygen        atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—;        and R^(1A) represents a C₃₋₇ cycloalkyl group, a C₂₋₆        heterocycloalkyl group, an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group which may have a protective        group, an amino group which may have a protective group, a C₁₋₆        alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, a        halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may        have a protective group, a carboxy group which may have a        protective group, a C₂₋₇ alkoxycarbonyl group, a cyano group and        a nitro group, or a heteroaryl group which may have a        substituent selected from the group consisting of a halogen atom        and a C₁₋₆ alkyl group;    -   X represents a single bond, an oxygen atom or a sulfur atom;    -   Y¹ represents a C₁₋₆ alkylene group which may be substituted by        a hydroxy group which may have a protective group, or a C₂₋₆        alkenylene group;    -   Z¹ represents —R^(1B), —COR^(1C), —SO₂R^(1C),        —CON(R^(1D))R^(1E), —SO₂NHR^(1F) or —C(═NR^(1G))N(R^(1H))R^(1I);    -   R^(1C) represents an aryl group which may have the same or        different 1 to 3 substituents selected from the group consisting        of a halogen atom, a hydroxy group which may have a protective        group, an amino group which may have a protective group, a C₁₋₆        alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy        group, a heteroaryl group which may have a substituent selected        from the group consisting of a halogen atom, an amino group        which may have a protective group and a C₁₋₆ alkyl group, or a        C₁₋₆ alkyl group which may have the same or different 1 to 5        groups selected from the following substituent group (ii);    -   R¹⁴, R^(1B), R^(1D), R^(1E) and R^(1F) are the same or        different, and each represents a hydrogen atom, an aryl group        which may have the same or different 1 to 3 substituents        selected from the group consisting of a halogen atom, a hydroxy        group which may have a protective group, an amino group which        may have a protective group, a C₁₋₆ alkylsulfonylamino group, a        C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group        which may have a substituent selected from the group consisting        of a halogen atom, an amino group which may have a protective        group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may        have the same or different 1 to 5 groups selected from the        following substituent group (ii), or both of R¹⁴ and R^(1B) bind        together with the neighboring nitrogen atom to form a C₂₋₆        cyclic amino group which may have a substituent selected from        the group consisting of a hydroxy group which may have a        protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo        group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl)        group which may have a protective group and a C₁₋₆        alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, or both of        R^(1D) and R^(1E) bind together with the neighboring nitrogen        atom to form a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group which may have a protective group, a carbamoyl group, a        C₁₋₆ alkyl group, an oxo group, a carbamoyl (C₁₋₆ alkyl) group,        a hydroxy(C₁₋₆ alkyl) group which may have a protective group        and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group;    -   R^(1G), R^(1H) and R^(1I) are the same or different, and each        represents a hydrogen atom, a cyano group, a carbamoyl group, a        C₂₋₇ acyl group, a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇        alkoxycarbonyl) group, a nitro group, a C₁₋₆ alkylsulfonyl        group, a sulfamide group, a carbamimidoyl group, or a C₁₋₆ alkyl        group which may have the same or different 1 to 5 groups        selected from the following substituent group (ii), or both of        R^(1G) and R^(1H) bind to form an ethylene group, or both of        R^(1H) and R^(1I) bind together with the neighboring nitrogen        atom to form a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group which may have a protective group, a carbamoyl group, a        C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a        hydroxy(C₁₋₆ alkyl) group which may have a protective group and        a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group;    -   R³, R⁵ and R⁶ are the same or different, and each represents a        hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆        alkoxy group; and    -   substituent group (ii) consists of a hydroxy group which may        have a protective group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio        group, an amino group which may have a protective group, a mono        or di(C₁₋₆ alkyl)amino group which may have a protective group,        a mono or di[hydroxy(C₁₋₆ alkyl)]amino group which may have a        protective group, an ureido group, a sulfamide group, a mono or        di(C₁₋₆alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide        group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group,        a C₁₋₆ alkylsulfonyl group, a carboxy group which may have a        protective group, a C₂₋₇ alkoxycarbonyl group,        —CON(R^(1J))R^(1K) in which R^(1J) and R^(1K) are the same or        different, and each represents a hydrogen atom or a C₁₋₆ alkyl        group which may have the same or different 1 to 3 substituents        selected from the group consisting of a hydroxy group which may        have a protective group, an amino group which may have a        protective group, a mono or di(C₁₋₆ alkyl)amino group which may        have a protective group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino        group which may have a protective group, an ureido group, a mono        or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆        alkylsulfonylamino group and a carbamoyl group, or both of        R^(1J) and R^(1K) bind together with the neighboring nitrogen        atom to form a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group which may have a protective group, a carbamoyl group, a        C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a        hydroxy(C₁₋₆ alkyl) group which may have a protective group and        a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an        aryl(C₁₋₆ alkoxy) group which may have the same or different 1        to 3 substituents selected from the group consisting of a        halogen atom, a hydroxy group which may have a protective group,        an amino group which may have a protective group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆        alkylthio) group which may have the same or different 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxy group which may have a protective group, an        amino group which may have a protective group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl        group, a C₂₋₆ heterocycloalkyl group, an aryl group which may        have the same or different 1 to 3 substituents selected from the        group consisting of a halogen atom, a hydroxy group which may        have a protective group, an amino group which may have a        protective group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl        group and a C₁₋₆ alkoxy group, a heteroaryl group which may have        a substituent selected from the group consisting of a halogen        atom, an amino group which may have a protective group and a        C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a        substituent selected from the group consisting of a hydroxy        group which may have a protective group, a carbamoyl group, a        C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆alkyl) group, a        hydroxy(C₁₋₆ alkyl) group which may have a protective group and        a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a        C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl        group as a substituent, or a salt thereof; and the like.

In the present invention, the term “C₁₋₆ alkyl group” means astraight-chained or branched alkyl group having 1 to 6 carbon atoms suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “C₁₋₆ alkylene group” means astraight-chained or branched alkylene group having 1 to 6 carbon atomssuch as a methylene group, an ethylene group, a trimethylene group, atetramethylene group, a propylene group, a 1,1-dimethylethylene group orthe like; the term “hydroxy(C₁₋₆ alkyl) group” means the above C₁₋₆alkyl group substituted by a hydroxy group; the term “C₂₋₆ alkyl groupsmeans a straight-chained or branched alkyl group having 2 to 6 carbonatoms such as an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a neopentyl group, a tert-pentylgroup, a hexyl group or the like; the term “hydroxy(C₂₋₆ alkyl) group”means the above C₂₋₆ alkyl group substituted by a hydroxy group, such asa 2-hydroxyethyl group, a 3-hydroxypropyl group or the like; the term“C₁₋₆ alkoxy group” means a straight-chained or branched alkoxy grouphaving 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group, a butoxy group, an isobutoxy group,a sec-butoxy group, a tert-butoxy group, a pentyloxy group, anisopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, ahexyloxy group or the like; the term “C₁₋₆ alkoxy-substituted (C₁₋₆alkyl) group” means the above C₁₋₆ alkyl group substituted by the aboveC₁₋₆ alkoxy group; the term “C₁₋₆ alkoxy-substituted (C₁₋₆ alkoxy)group” means the above C₁₋₆ alkoxy group substituted by the above C₁₋₆alkoxy group, such as a methoxymethoxy group or the like; the term “C₂₋₆alkenyl group” means a straight-chained or branched alkenyl group having2 to 6 carbon atoms such as a vinyl group, an allyl group, a 1-propenylgroup, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a2-methylallyl group or the like; the term “C₂₋₆ alkenylene group” meansa straight-chained or branched alkenylene group having 2 to 6 carbonatoms such as a vinylene group, a 1-propenylene group, a 2-propenylenegroup or the like; the term “C₂₋₆ alkenyloxy group” means the above C₁₋₆alkoxy group except for a methoxy group which has an unsaturated bond,such as an allyloxy group or the like; the term “C₁₋₆ alkylthio group”means a straight-chained or branched alkylthio group having 1 to 6carbon atoms such as a methylthio group, an ethylthio group, apropylthio group, an isopropylthio group, a butylthio group, anisobutylthio group, a sec-butylthio group, a tert-butylthio group, apentylthio group, an isopentylthio group, a neopentylthio group, atert-pentylthio group, a hexylthio group or the like; the term“carbamoyl(C₁₋₆ alkyl) group” means the above C₁₋₆ alkyl groupsubstituted by a carbamoyl group; the term “mono or di(C₁₋₆ alkyl)aminogroup” means an amino group mono-substituted by the above C₁₋₆ alkylgroup or di-substituted by the same or different C₁₋₆ alkyl groups asdefined above; the term “mono or di[hydroxy(C₁₋₆ alkyl)]amino group”means an amino group mono-substituted by the above hydroxy(C₁₋₆ alkyl)group or di-substituted by the same or different hydroxy(C₁₋₆ alkyl)groups as defined above; the term “mono or di(C₁₋₆ alkyl)ureido group”means an ureido group mono-substituted by the above C₁₋₆ alkyl group ordi-substituted by the same or different C₁₋₆ alkyl groups as definedabove;

-   -   the term “mono or di(C₁₋₆ alkyl)sulfamide group” means a        sulfamide group mono-substituted by the above C₁₋₆ alkyl group        or di-substituted by the same or different C₁₋₆ alkyl groups as        defined above; the term “C₂₋₇ acyl group” means a        straight-chained or branched acyl group having 2 to 7 carbon        atoms, such as an acetyl group, a propionyl group, a butyryl        group, an isobutyryl group, a valeryl group, a pivaloyl group, a        hexanoyl group or the like; the term “C₂₋₇ acylamino group”        means an amino group substituted by the above C₂₋₇ acyl group;        the term “C₁₋₆ alkylsulfonyl group” means a straight-chained or        branched alkylsulfonyl group having 1 to 6 carbon atoms, such as        a methanesulfonyl group, an ethanesulfonyl group or the like;        the term “C₁₋₆ alkylsulfonylamino group” means an amino group        substituted by the above C₁₋₆ alkylsulfonyl group; the term        “C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group” means        the above C₁₋₆ alkyl group substituted by the above C₁₋₆        alkylsulfonylamino group; the term “C₃₋₇ cycloalkyl group” means        a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a        cyclohexyl group or a cycloheptyl group; the term “C₃₋₇        cycloalkyl-substituted (C₁₋₆ alkyl) group” means the above C₁₋₆        alkyl group substituted by the above C₃₋₇ cycloalkyl group; the        term “C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group” means the        above C₁₋₆ alkoxy group except for a methoxy group substituted        by the above C₃₋₇ cycloalkyl group; the term “C₂₋₆        heterocycloalkyl group” means the above C₃₋₇ cycloalkyl group        containing the same or different 1 or 2 hetero atoms other than        the binding position selected from a nitrogen atom, an oxygen        atom and a sulfur atom in the ring, which is derived from        morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran,        aziridine, azetidine, pyrrolidine, imidazolidine, oxazoline,        piperidine, piperazine, pyrazolidine or the like; the term        “halogen atom” means a fluorine atom, a chlorine atom, a bromine        atom or an iodine atom; the term “halo(C₁₋₆ alkyl) group” means        the above C₁₋₆ alkyl group substituted by the same or different        1 to 5 halogen atoms as defined above, such as a trifluoromethyl        group, a pentafluoroethyl group or the like; the term “halo(C₁₋₆        alkoxy) group” means the above C₁₋₆ alkoxy group substituted by        the same or different 1 to 5 halogen atoms as defined above; the        term “C₂₋₇ alkoxycarbonyl group” means a straight-chained or        branched alkoxycarbonyl group having 2 to 7 carbon atoms, such        as a methoxycarbonyl group, an ethoxycarbonyl group, a        propoxycarbonyl group, an isopropoxycarbonyl group, a        butoxycarbonyl group, an isobutyloxycarbonyl group, a        sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a        pentyloxycarbonyl group, an isopentyloxycarbonyl group, a        neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, a        hexyloxycarbonyl group or the like; the term “aryl group” means        mono to tricyclic aromatic hydrocarbon group such as a phenyl        group, a naphthyl group, or the like; the term “aryl(C₁₋₆ alkyl)        group” means the above C₁₋₆ alkyl group substitute by the above        aryl group; the term aryl(C₁₋₆ alkoxy) group” means the above        C₁₋₆ alkoxy group substitute by the above aryl group; the term        “aryl(C₁₋₆alkylthio) group” means the above C₁₋₆ alkylthio group        substitute by the above aryl group; the term “aryl(C₂₋₇        alkoxycarbonyl) group” means the above C₂₋₇ alkoxycarbonyl group        substitute by the above aryl group, such as a benzyloxycarbonyl        group or the like; the term “heteroaryl group” means a 5 or        6-membered heteroaryl group containing the same or differenr 1        to 4 hetero atoms other than the binding position selected from        a nitrogen atom, an oxygen atom and a sulfur atom in the ring,        which is derived from thiazole, oxazole, isothiazole,        isooxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,        thiophene, imidazole, pyrazole, oxadiazole, thiodiazole,        tetrazole, furazan or the like; the term “C₂₋₆ cyclic amino        group” means a 5 or 6-membered monocyclic amino group having 2        to 6 carbon atoms which may contain one hetero atom other than        the nitrogen atom at the binding position selected from a        nitrogen atom, an oxygen atom and a sulfur atom in the ring,        such as a morpholino group, a thiomorpholino group, a        1-aziridinyl group, a 1-azetidinyl group, a 1-pyrrolidinyl        group, a piperidino group, a 1-imidazolidinyl group, a        1-piperazinyl group, a pyrazolidinyl group or the like; the term        “C₁₋₄ aromatic cyclic amino group” means a 5-membered aromatic        monocyclic amino group having 1 to 4 carbon atoms which may        contain 1 to 3 nitrogen atoms other than the nitrogen atom at        the binding position, such as a 1-imidazolyl group, a 1-pyrrolyl        group, a pyrazolyl group, a 1-tetrazolyl group or the like; the        term “hydroxy-protective group” means a hydroxy-protective group        used in general organic synthesis such as a benzyl group, a        methoxymethyl group, an acetyl group, a pivaloyl group, a        benzoyl group, a tert-butyldimethylsilyl group, a        triisopropylsilyl group, an allyl group or the like; the term        “amino-protective group” means an amino-protective group used in        general organic synthesis such as a benzyloxycarbonyl group, a        tert-butoxycarbonyl group, a benzyl group, a trifluoroacetyl        group or the like; and the term “carboxy-protective group” means        a carboxy-protective group used in general organic synthesis        such as a benzyl group, a tert-butyldimethylsilyl group, an        allyl group or the like.

In the present invention, for example, R¹ is preferably a hydrogen atomor a hydroxy(C₂₋₆ alkyl) group, and is more preferably a hydrogen atom;T is preferably a group of the formula:

or a group of the formula:

Q is preferably a C₁₋₆ alkyl group or a halo(C₁₋₆ alkyl) group, and ismore preferably a C₁₋₆ alkyl group; the C₁₋₆ alkyl group in Q ispreferably an ethyl group or an isopropyl group, and is more preferablyan isopropyl group; X is preferably a single bond or an oxygen atom; Yis preferably a C₁₋₆ alkylene group or a C₂₋₆ alkenylene group, and ismore preferably a C₁₋₆ alkylene group; the C₁₋₆ alkylene group in Y ispreferably an ethylene group, a trimethylene group or a tetramethylenegroup, and is more preferably an ethylene group or a trimethylene group.Z is preferably —R^(B), —COR^(C), —CON(R^(D))R^(E) or—C(═NR^(G))N(R^(H))R^(I), and is more preferably —R^(B) or—CON(R^(D))R^(E), and is most preferably —R^(B); R^(B) in Z ispreferably a C₁₋₆ alkyl group which has the same or different 1 to 5groups selected from the above substituent group (iA), and is morepreferably a C₁₋₆ alkyl group having a carbamoyl group; R^(D) in Z ispreferably a hydrogen atom; R^(E) is preferably a C₁₋₆ alkyl group whichhas the same or different 1 to 5 groups selected from the abovesubstituent group (iB); R^(G) in Z is preferably a hydrogen atom or aC₁₋₆ alkylsulfonyl group; R^(H) is preferably a hydrogen atom; R^(I) ispreferably a hydrogen atom or a C₁₋₆ alkyl group which may have the sameor different 1 to 5 groups selected from the above substituent group(iC); and R^(C) in Z is preferably a C₁₋₆ alkyl group which has the sameor different 1 to 5 groups selected from the above substituent group(iD). R⁴ is preferably a hydrogen atom; R² is preferably a hydrogenatom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, aC₁₋₆alkoxy-substituted (C₁₋₆alkoxy) group, a C₃₋₇ cycloalkyl-substituted(C₂₋₆ alkoxy) group or a group of the general formula: -A-R^(A) in whichA and R^(A) have the same meanings as defined above, and is morepreferably a hydrogen atom, a chlorine atom, a fluorine atom or a methylgroup; and R³, R⁵ and R⁶ are preferably a hydrogen atom or a halogenatom, and all of them are more preferably a hydrogen atom.

As concrete compounds in the present invention, compounds described inExamples 1-187 are examplified. Specifically, the following compounds orpharmaceutically acceptable salts thereof are preferable.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared according to the followingprocedure:

wherein L¹ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group or the like; L² represents MgBr, MgCl, MgI, ZnI,ZnBr, ZnCl or a lithium atom; R represents a C₁₋₆ alkyl group, ahalo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group ora C₃₋₇ cycloalkyl group; R⁰ represents a C₁₋₆ alkyl group; one of Q³ andT³ represents a hydroxy group, the other represents a C₁₋₆alkyl group, ahalo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group ora C₃₋₇ cycloalkyl group; and R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹² R¹⁴, Q,Q², T, T², X, Y, Y¹, Z and Z¹ have the same meanings as defined above.Process 1-1

A compound represented by the above general formula (VI) can be preparedby condensing a benzyl compound represented by the above general formula(IV) with a ketoacetate represented by the above general formula (V) inthe presence of a base such as sodium hydride or potassium tert-butoxidein an inert solvent. As the inert solvent used in the reaction, forexample, 1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 1-2

A benzylpyrazole derivative represented by the above general formula(III) can be prepared by condensing a compound represented by the abovegeneral formula (VI) with a hydrazine compound represented by the abovegeneral formula (VII) or a monohydrate thereof, or a salt thereof in thepresence or absence of a base in an inert solvent, and introducing ahydroxy-protective group in the usual way as occasion demands. As theinert solvent used in the condensing reaction, for example, toluene,tetrahydrofuran, chloroform, methanol, ethanol, a mixed solvent thereofand the like can be illustrated, and as the base, for example,triethylamine, N,N-diisopropylethylamine, pyridine, sodium methoxide,sodium ethoxide and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature. The obtainedbenzylpyrazole derivative represented by the above general formula (III)can be also used in the subsequent process after suitably convertinginto a salt thereof in the usual way.

Process 1-3

A compound represented by the above general formula (X) can be preparedby condensing dithiocarbonate ester compound represented by the abovegeneral formula (VIII) with a ketone compound represented by the abovegeneral formula (IX) in the presence of a base such as sodium amide inan inert solvent. As the inert solvent used in the reaction, forexample, toluene and the like can be illustrated. The reactiontemperature is usually from −20° C. to room temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 1-4

A benzyloxypyrazole derivative represented by the above general formula(XI) can be prepared by condensing a compound represented by the abovegeneral formula (X) with a hydrazine compound represented by the abovegeneral formula (VII) or a monohydrate thereof, or a salt thereof in thepresence of a base such as triethylamine or N,N-diisopropylethylamine inan inert solvent, and introducing a hydroxy-protective group in theusual way as occasion demands. As the inert solvent used in thecondensing reaction, for example, acetonitrile and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 1 hour to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 1-5

A pyrazole aldehyde derivative represented by the above general formula(XII) can be prepared by subjecting a compound represented by the abovegeneral formula (XI) to Vilsmeier reaction using phosphorus oxychlorideand N,N-dimethylformamide in a various solvent. As the solvent used inthe reacion, for example, N,N-dimethylformamide and the like can beillustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 1-6

A compound represented by the above general formula (XIV) can beprepared by condensing a compound represented by the above generalformula (XII) with a Grignard reagent, a Reformatsky reagent or alithium reagent represented by the above general formula (XIII) in aninert solvent. As the inert solvent used in the reaction, for example,tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually from −78° C. to roomtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature.

Process 1-7

A benzylpyrazole derivative represented by the above general formula(III) can be prepared by subjecting a compound represented by the abovegeneral formula (XIV) to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon powder in the presence or absence ofan acid such as hydrochloric acid in an inert solvent, and in case thata compound represented by the above general formula (XIV) has any sulfuratom, subjecting the resulting compound to acid treatment in an aqueoussolution of trifluoroacetic acid and dimethyl sulfide usually at 0° C.to reflux temperature for 30 minutes to 1 day as occasion demands. Asthe solvent used in the catalytic hydrogenation, for example, methanol,ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature. The obtainedbenzylpyrazole derivative represented by the above general formula (III)can be also used in the subsequent process after suitably convertinginto a salt thereof in the usual way.

Process 1-8

[1] In case that one of Q³ and T³ is a C₁₋₆ alkyl group, a C₁₋₆alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group in abenzylpyrazole derivative represented by the above general formula(III), a corresponding compound represented by the above general formula(II) of the present invention can be prepared by subjecting acorresponding benzylpyrazole derivative represented by the above generalformula (III) to glycosidation using acetobromo-α-D-glucose,acetobromo-α-D-galactose, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosylbromide or 2,3,4,6-tetra-O-pivaloyl-α-D-galactopyranosyl bromide in thepresence of a base such as silver carbonate, sodium hydride or the likein an inert solvent. As the inert solvent used in the reaction, forexample, tetrahydrofuran, dimethoxyethane, N,N-dimethylformamide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature.

[2] In case that one of Q³ and T³ is a halo(C₁₋₆ alkyl) group in abenzylpyrazole derivative represented by the above general formula(III), a corresponding compound represented by the above general formula(II) of the present invention can be prepared by subjecting acorresponding benzylpyrazole derivative represented by the above generalformula (III) to glycosidation using acetobromo-α-D-glucose,acetobromo-α-D-galactose, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosylbromide or 2,3,4,6-tetra-O-pivaloyl-α-D-galactopyranosyl bromide in thepresence of a base such as potassium carbonate or the like in an inertsolvent. As the inert solvent used in the reaction, for example,tetrahydrofuran, acetonitrile, a mixed solvent thereof and the like canbe illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 1 day, varying based on a used starting material, solvent andreaction temperature.

[3] In case that one of Q³ and T³ is a C₂₋₆ alkyl group, a C₁₋₆alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group in abenzylpyrazole derivative represented by the above general formula(III), a corresponding compound represented by the above general formula(II) of the present invention can be also prepared by subjecting acorresponding benzylpyrazole derivative represented by the above generalformula (III) to glycosidation using acetobromo-α-D-glucose,acetobromo-α-D-galactose, 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosylbromide or 2,3,4,6-tetra-O-pivaloyl-α-D-galactopyranosyl bromide in thepresence of a base such as sodium hydroxide, potassium hydroxide,potassium carbonate or the like and a phase transfer catalyst such asbenzyltri(n-butyl)ammonium chloride, benzyltri-(n-butyl)ammoniumbromide, tetra(n-butyl)ammonium hydrogen sulfate or the like in an inertsolvent containing water. As the inert solvent used in the reaction,dichloromethane, toluene, benzotrifluoride, a mixed solvent thereof andthe like can be illustrated. The reaction temperature is usually from 0°C. to reflux temperature, and the reaction time is usually from 30minutes to 1 day, varying based on a used starting material, solvent andreaction temperature.

The obtained glycosidated benzylpyrazole derivative represented by theabove general formula (II) can be also used in the subsequent processafter suitably converting into a salt thereof and separating in theusual way.

Process 1-9

A pyrazole derivative represented by the above general formula (I) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (II) to alkaline hydrolysis,and removing a protective group or subjecting a nitro group of theresulting compound to reduction as occasion demands. As the solvent usedin the hydrolysis reaction, for example, methanol, ethanol,tetrahydrofuran, water, a mixed solvent thereof and the like can beillustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. As mentioned above, in case of compounds having aprotective group in R¹¹, R¹², R¹⁴, Y¹ and/or Z after the hydrolysis, theprotective group can be suitably removed in the usual way. Furthermore,after the completion of the above reaction, compounds having a nitrogroup in R² represented by the above general formula (I) can be alsoderived into a corresponding compound having an amino group by catalyticreduction using a platinum catalyst such as platinum oxide in an inertsolvent such as ethyl acetate at usually room temperature to refluxtemperature for usually 30 minutes to 1 day in the usual way.

Among the compounds represented by the above general formula (III) asstarting materials, there can be the following three tautomers incompounds wherein R¹¹ is a hydrogen atom, varying based on difference inthe reaction conditions, and the compounds represented by the abovegeneral formula (III) include all the compounds:

wherein R, R³, R⁵, R⁶, R¹², R¹⁴ R¹¹ X, Y¹ and Z¹ have the same meaningsas defined above.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkylgroup, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group or an aryl(C₁₋₆alkyl) group which may have the same or different 1 to 3 substituentsselected from the group consisting of a halogen atom, a hydroxy group,an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring,for example, can be prepared according to the following procedure:

wherein L³ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group or the like; R²¹ represents a C₁₋₆ alkyl group,a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group which may have aprotective group, a C₃₋₇ cycloalkyl group, a C₃₋₇ cycloalkyl-substituted(C₁₋₆ alkyl) group or an aryl(C₁₋₆ alkyl) group which may have the sameor different 1 to 3 substituents selected from the group consisting of ahalogen atom, a hydroxy group which may have a protective group, anamino group which may have a protective group, a C₁₋₆ alkyl group and aC₁₋₆ alkoxy group on the ring; R³¹ represents a C₁₋₆ alkyl group, a C₂₋₆alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, aC₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group or an aryl(C₁₋₆ alkyl)group which may have the same or different 1 to 3 substituents selectedfrom the group consisting of a halogen atom, a hydroxy group, an aminogroup, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring; and R²,R³, R⁴, R⁵ R⁶, R¹², R¹⁴, Q, Q, Q², T, T², X, Y, Y¹, Z and Z have thesame meanings as defined above.Process 2

A pyrazole derivative represented by the above general formula (Ia) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIa) to hydrolysis accordingto a similar method to that described in the above process 1-9 andN-alkylation using an alkylating agent represented by the above generalformula (XV) in the presence of a base such as cesium carbonate orpotassium carbonate in an inert solvent, and in case of compounds havinga protective group, suitably removing the protective group in the usualway as occasion demands. As the inert solvent used in the N-alkylation,for example, acetonitrile, ethanol, 1,2-dimethoxyethane,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 10 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹, R⁴ and Z represent a hydrogenatom, for example, can be also prepared according to the followingprocedure:

wherein L represents a leaving group such as a mesyloxy group, atosyloxy group or the like; and R², R³, R⁵, R⁶, R¹², Q, Q², T, T², X, Yand Y¹ have the same meanings as defined above.Process 3-1

A compound represented by the above general formula (XVII) can beprepared by subjecting a compound represented by the above generalformula (XVI) to catalytic hydrogenation using a palladium catalyst suchas palladium-carbon powder in an inert solvent to remove the benzylgroup. As the solvent used in the catalytic hydrogenation, for example,methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 1 hour to 2 days, varying based on a usedstarting material, solvent and reaction temperature.

Process 3-2

A compound represented by the above general formula (XVIII) can beprepared by introducing a leaving group into a compound represented bythe above general formula (XVII) using an acid chloride such as mesylchloride or tosyl chloride in the presence of a base such astriethylamine or N,N-diisopropylethylamine in an inert solvent. As thesolvent used in the introducing reaction, for example, dichloromethane,ethyl acetate, tetrahydrofuran, pyridine, a mixed solvent thereof andthe like can be illustrated. The reaction temperature is usually from 0°C. to room temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

Process 3-3

A compound represented by the above general formula (XIX) can beprepared by subjecting a compound represented by the above generalformula (XVIII) to azidation using an azidating agent such as sodiumazide in an inert solvent. As the solvent used in the azidation, forexample, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylimidazolidinone, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Process 3-4

A compound represented by the above general formula (IIb) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (XIX) to catalytic hydrogenation using a palladiumcatalyst such as palladium-carbon powder in an inert solvent. As thesolvent used in the catalytic hydrogenation, for example,tetrahydrofuran, methanol, ethanol, ethyl acetate, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from room temperature to reflux temperature, and the reactiontime is usually from 30 minutes to 1 day, varying based on a usedstarting material, solvent and reaction temperature.

Process 3-5

A compound represented by the above general formula (XX) can be preparedby subjecting a compound represented by the above general formula (XIX)to alkaline hydrolysis, and removing the protective group in the usualway as occasion demands. As the solvent used in the hydrolysis reaction,for example, methanol, ethanol, tetrahydrofuran, water, a mixed solventthereof and the like can be illustrated. As the base, for example,sodium hydroxide, sodium methoxide, sodium ethoxide, methylamine,dimethylamine and the like can be illustrated. The reaction temperatureis usually from 0° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature. In case of compounds havinga protective group in R¹² and/or Y¹ after the hydrolysis, the protectivegroup can be suitably removed in the usual way as the process 1-9.

Process 3-6

A pyrazole derivative represented by the above general formula (Ib) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIb) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In case of compounds having a protective group in R¹²and/or Y¹ after the hydrolysis, the protective group can be suitablyremoved in the usual way as the process 1-9.

Process 3-7

A pyrazole derivative represented by the above general formula (Ib) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (XX) to catalytic hydrogenationusing a palladium catalyst such as palladium-carbon powder in an inertsolvent. As the solvent used in the catalytic hydrogenation, forexample, tetrahydrofuran, methanol, ethanol, ethyl acetate, a mixedsolvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 30 minutes to 1 day, varying based ona used starting material, solvent and reaction temperature.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ and R⁴ represent a hydrogenatom; and Z represents —COR^(C), —SO₂R^(C), —CON(R^(D))R^(E) or—C(═NR^(2G))NHR^(2H), for example, can be prepared according to thefollowing procedures:

wherein L⁵ represents a leaving group such as a pyrazolyl group, amethylthio group, a benzotriazolyl group or the like; R^(2G) and R^(2H)are the same or different, and each represents a hydrogen atom, abenzyloxycarbonyl group or a tert-butoxycarbonyl group; Z² represents—COR^(1C), —SO₂R^(1C), —CONHR^(1D) or —C(═NR^(2G))NHR^(2H); Z^(A)represents —COR^(1C), SO₂R^(1C), CONHR^(ID) or —C(═NR^(2G))NHR^(2H); andR^(1C), R^(1D), R^(1E), R², R³, R⁵, R⁶, R¹², R^(D), R^(E), Q, Q², T, T²,X, Y and Y¹ have the same meanings as defined above.Process 4-1

A compound represented by the above general formula (IIc) can beprepared from a compound represented by the above general formula (IIb)by treating according to the following methods 1-4, and removing theprotective group in the usual way as occasion demands.

<Method 1>

A compound represented by the above general formula (IIb) is allowed toreact with an acid chloride represented by the above general formula(XXI) or (XXII) in the presence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo(5.4.0]unde-7-cene in an inert solvent such asdichloromethane, ethyl acetate, tetrahydrofuran, pyridine, acetonitrileor a mixed solvent thereof at usually 0° C. to reflux temperature forusually 30 minutes to 1 day.

<Method 2>

A compound represented by the above general formula (IIb) is allowed toreact with an isocyanate compound represented by the above generalformula (XXIII) in the presence or absence of a base such astriethylamine, N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo[5.4.0]unde-7-cene in an inert solvent such asdichloromethane, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile,toluene or a mixed solvent thereof at usually 0° C. to refluxtemperature for usually 30 minutes to 1 day.

<Method 3>

A compound represented by the above general formula (IIb) is allowed toreact with a carboxylic acid compound represented by the above generalformula (XXIV) after suitably adding 1-hydroxybenzotriazole as occasiondemands in the presence of a condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride ordicyclohexylcarbodiimide and in the presence or absence of a base suchas triethylamine or N,N-diisopropylethylamine in an inert solvent suchas N,N-dimethylformamide, dichloromethane or a mixed solvent thereof atusually 0° C. to reflux temperature for usually 1 hour to 2 days.

<Method 4>

A compound represented by the above general formula (IIb) is allowed toreact with a guanidylating reagent represented by the above generalformula (XXV) such as N-(benzyloxycarbonyl)-1H-pyrazol-1-carboxamidinein an inert solvent such as tetrahydrofuran, methanol, ethanol, toluene,N,N-dimethylformamide or a mixed solvent thereof at usually roomtemperature to reflux temperature for usually 1 hour to 5 days.

Process 4-2

A pyrazole derivative represented by the above general formula (Ic) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIc) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In case of compounds having a protective group in R¹², Y¹and/or Z² after the hydrolysis, the protective group can be suitablyremoved in the usual way as the process 1-9.

Process 5-1

An activated ester compound represented by the above general formula(XXVII) can be prepared by condensing a compound represented by theabove general formula (IIb) with an agent for making an activated esterrepresented by the above formula (XXVI) in the presence of a base suchas triethylamine, N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo-[5.4.0]unde-7-cene in an inert solvent. As the solventused in the condensing reaction, for example, dichloromethane,tetrahydrofuran, ethyl acetate, acetonitrile, pyridine, a mixed solventthereof and the like can be illustrated. The reaction temperature isusually from 0° C. to reflux temperature, and the reaction time isusually from 30 minutes to 1 day, varying based on a used startingmaterial, solvent and reaction temperature.

Process 5-2

An pyrazole derivative represented by the above general formula (IId) ofthe present invention can be prepared by condensing a compoundrepresented by the above general formula (XXVII) with an amine compoundrepresented by the above general formula (XXVIII) or a salt thereof inthe presence or absence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]unde-7-cene,sodium hydride, potassium tert-butoxide, potassium carbonate or cesiumcarbonate in an inert solvent, and removing the protective group in theusual way as occasion demands. As the solvent used in the condensingreaction, for example, dichloromethane, methanol, ethanol,tetrahydrofuran, ethyl acetate, acetonitrile, pyridine,N,N-dimethylformamide, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 30 minutesto 2 days, varying based on a used starting material, solvent andreaction temperature.

Process 5-3

A pyrazole derivative represented by the above general formula (Id) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IId) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In case of compounds having a protective group in R¹²,R^(1D), R^(1E) and/or Y¹ after the hydrolysis, the protective group canbe suitably removed in the usual way as the process 1-9.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a hydrogen atom; andZ represents R^(B), for example, can be also prepared according to thefollowing procedures:

wherein R¹⁴, R^(1B), R², R³, R⁴, R⁵, R⁶R¹², R^(B), L⁴, Q, Q², T, T², X,Y and Y¹ have the same meanings as defined above.Process 6

A pyrazole derivative represented by the above general formula (Ie) ofthe present invention can be prepared by condensing a compoundrepresented by the above general formula (XVIII) with an amine compoundrepresented by the above general formula (XXIX) or a salt thereof in thepresence or absence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]unde-7-cene,sodium hydride, potassium tert-butoxide, potassium carbonate or cesiumcarbonate in an inert solvent after adding sodium iodide as occasiondemands, subjecting the resulting compound to alkaline hydrolysis, andremoving the protective group in the usual way as occasion demands. Asthe solvent used in the condensing reaction, for example, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone,methanol, ethanol, 2-propanol, tetrahydrofuran, a mixed solvent thereofand the like can be illustrated. The reaction temperature is usuallyfrom room temperature to reflux temperature, and the reaction time isusually from 1 hour to 5 days, varying based on a used startingmaterial, solvent and reaction temperature. As the solvent used in thehydrolysis reaction, for example, methanol, ethanol, tetrahydrofuran,water, a mixed solvent thereof and the like can be illustrated. As thebase, for example, sodium hydroxide, sodium methoxide, sodium ethoxide,methylamine, dimethylamine and the like can be illustrated. The reactiontemperature is usually from 0° C. to reflux temperature, and thereaction time is usually from 30 minutes to 1 day, varying based on aused starting material, solvent and reaction temperature. In case ofcompounds having a protective group in R¹², R¹⁴, R^(1B) and/or Y¹ afterthe hydrolysis, the protective group can be suitably removed in theusual way as the process 1-9.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a hydrogen atom; R⁴represent a C₁₋₆ alkyl group which may have the same or different 1 to 5groups selected from the above substituent group (i); and Z represents ahydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1to 5 groups selected from the above substituent group (i), —COR^(C),—SO₂R^(C), —CONHR^(D) or —C(═NR^(2G))NHR^(2H), for example, can be alsoprepared according to the following procedures:

wherein L⁶ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group or the like; W represents a 2-nitro group, a4-nitro group or a 2,4-dinitro group; R²⁴ represents a C₁₋₆ alkyl groupwhich may have the same or different 1 to 5 groups selected from theabove substituent group (ii); R³⁴ and the neighboring carbon atom formR²⁴ after reduction; both of R^(4B) and R^(5B) bind together with theneighboring carbon atom to form R²⁴ having a branched C₃₋₆ alkyl groupafter reduction; R^(4A) represents a C₁₋₆ alkyl group which may have thesame or different 1 to 5 groups selected from the above substituentgroup (i); Z³ represents a C₁₋₆ alkyl group which may have the same ordifferent 1 to 5 groups selected from the above substituent group (ii),—COR^(1C), —SO₂R^(1C), —CONHR^(1D) or —C(═NR^(2G))NHR^(2H); Z^(B)represents a C₁₋₆ alkyl group which may have the same or different 1 to5 groups selected from the above substituent group (i), —COR^(C),—SO₂R^(C), —CONHR^(D) or —C(═NR^(2G))NHR^(2H); and L⁵, R^(1C), R^(1D),R^(2G), R^(2H), R², R³, R⁵, R⁶, R¹², Q, Q², T, T², X, Y and Y¹ have thesame meanings as defined above.Process 7-1

A compound represented by the above general formula (IIe) of the presentinvention can be prepared from a compound represented by the abovegeneral formula (IIb) by treating according to the following methods1-3.

<Method 1>

1) A compound represented by the above general formula (IIb) is allowedto react with an acid chloride represented by the above general formula(XXX) in the presence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo[5.4.0]unde-7-cene in an inert solvent such asdichloromethane, ethyl acetate, tetrahydrofuran, pyridine, acetonitrileor a mixed solvent thereof at usually 0° C. to room temperature forusually 30 minutes to 1 day to obtain the corresponding sulfonamidecompound.

2) The obtained sulfonamide compound is N-alkylated using an alkylatingagent represented by the above general formula (XXXI) after addingsodium iodide as occasion demands in the presence of a base such aspotassium carbonate, cesium carbonate or sodium hydride in an inertsolvent such as N,N-dimethylformamide, acetone, tetrahydrofuran,acetonitrile or a mixed solvent thereof at usually room temperature toreflux temperature for usually 1 hour to 2 days, or the obtainedsulfonamide compound is N-alkylated using an alcohol compoundrepresented by the above general formula (XXXII) in the presence of adiester of an azodicarboxylic acid such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate, and triphenylphosphine in an inert solventsuch as tetrahydrofuran, ethyl acetate, acetonitrile or a mixed solventthereof at usually room temperature to reflux temperature for usually 30minutes to 1 day to obtain the corresponding N,N-disubstitutedsulfonamide compound.

3-4) The obtained N,N-disubstituted sulfonamide compound is deprotectedusing a thiol reagent such as mercaptoacetic acid or thiophenol in thepresence of a base such as cesium carbonate or potassium carbonate in aninert solvent such as N,N-dimethylformamide, acetonitrile or a mixedsolvent thereof at usually room temperature to reflux temperature forusually 1 hour to 1 day to obtain the corresponding secondary aminecompound, and the protective group is removed in the usual way asoccasion demands.

<Method 2>

An aldehyde compound represented by the above general formula (XXXIII)or a ketone compound represented by the above general formula (XXXIV) isreductively aminated using a compound represented by the above generalformula (IIb) in the presence of a reducing agent such as sodiumcyanoborohydride or sodium triacetoxyborohydride in an inert solventsuch as tetrahydrofuran, 1,2-dichloroethane, acetic acid or a mixedsolvent thereof at usually room temperature to reflux temperature forusually 1 hour to 1 day.

<Method 3>

A compound represented by the above general formula (IIb) is N-alkylatedusing an alkylating agent represented by the above general formula(XXXI) after adding sodium iodide as occasion demands in the presence orabsence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine or 1,8-diazabicyclo-[5.4.0]unde-7-cene in an inert solvent suchas acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, methanol, ethanol, 2-propanol or a mixed solventthereof at usually room temperature to reflux temperature for usually 1hour to 5 days.

Process 7-2

1) A sulfonamide compound represented by the above general formula(XXXV) is N-alkylated using a compound represented by the above generalformula (XVII) in the presence of a diester of an azodicarboxylic acidsuch as diethyl azodicarboxylate or diisopropyl azodicarboxylate, andtriphenylphosphine in an inert solvent such as tetrahydrofuran, ethylacetate, acetonitrile or a mixed solvent thereof at usually roomtemperature to reflux temperature for usually 30 minutes to 1 day toobtain the corresponding N,N-disubstituted sulfonamide compound.

2-3) The obtained N,N-disubstituted sulfonamide compound is deprotectedusing a thiol reagent such as mercaptoacetic acid or thiophenol in thepresence of a base such as cesium carbonate or potassium carbonate in aninert solvent such as N,N-dimethylformamide, acetonitrile or a mixedsolvent thereof at usually room temperature to reflux temperature forusually 1 hour to 1 day to obtain the corresponding secondary aminecompound, and the protective group is removed in the usual way asoccasion demands to prepare a prazole derivative represented by theabove general formula (IIe) of the present invention.

Process 7-3

A pyrazole derivative represented by the above general formula (If) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIe) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In case of compounds having a protective group in R¹², R²⁴and/or Y¹ after the hydrolysis, the protective group can be suitablyremoved in the usual way as the process 1-9.

Process 7-4

A compound represented by the above general formula (IIf) of the presentinvention can be prepared from a compound represented by the abovegeneral formula (IIe) by treating according to the following methods1-6, and removing the protective group in the usual way as occasiondemands.

<Method 1>

A compound represented by the above general formula (IIe) is allowed toreact with an acid chloride represented by the above general formula(XXI) or (XXII) in the presence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo[5.4.0]unde-7-cene in an inert solvent such asdichloromethane, ethyl acetate, tetrahydrofuran, pyridine, acetonitrileor a mixed solvent thereof at usually 0° C. to reflux temperature forusually 30 minutes to 1 day.

<Method 2>

A compound represented by the above general formula (IIe) is allowed toreact with an isocyanate compound represented by the above generalformula (XXIII) in the presence or absence of a base such astriethylamine, N,N-diisopropylethylamine, pyridine or1,8-diazabicyclo[5.4.0]unde-7-cene in an inert solvent such asdichloromethane, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile,toluene or a mixed solvent thereof at usually 0° C. to refluxtemperature for usually 30 minutes to 1 day.

<Method 3>

A compound represented by the above general formula (IIe) is allowed toreact with a carboxylic acid compound represented by the above generalformula (XXIV) after suitably adding 1-hydroxybenzotriazole as occasiondemands in the presence of a condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride ordicyclohexylcarbodiimide and in the presence or absence of a base suchas triethylamine or N,N-diisopropylethylamine in an inert solvent suchas N,N-dimethylformamide, dichloromethane or a mixed solvent thereof atusually 0° C. to reflux temperature for usually 1 hour to 2 days.

<Method 4>

A compound represented by the above general formula (IIe) is allowed toreact with a guanidylating reagent represented by the above generalformula (XXV) such as N-(benzyloxycarbonyl)-1H-pyrazol-1-carboxamidinein an inert solvent such as tetrahydrofuran, methanol, ethanol, toluene,N,N-dimethylformamide or a mixed solvent thereof at usually roomtemperature to reflux temperature for usually 1 hour to 5 days.

<Method 5>

An aldehyde compound represented by the above general formula (XXXIII)or a ketone compound represented by the above general formula (XXXIV) isreductively aminated using a compound represented by the above generalformula (IIe) in the presence of a reducing agent such as sodiumcyanoborohydride or sodium triacetoxyborohydride in an inert solventsuch as tetrahydrofuran, 1,2-dichloroethane, acetic acid or a mixedsolvent thereof at usually room temperature to reflux temperature forusually 1 hour to 1 day.

<Method 6>

A compound represented by the above general formula (IIe) is N-alkylatedusing an alkylating agent represented by the above general formula(XXXI) after adding sodium iodide as occasion demands in the presence orabsence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine or 1,8-diazabicyclo-[5.4.0]unde-7-cene in an inert solvent suchas acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone, methanol, ethanol, 2-propanol or a mixed solventthereof at usually room temperature to reflux temperature for usually 1hour to 5 days.

Process 7-5

A pyrazole derivative represented by the above general formula (Ig) ofthe present invention can be prepared by subjecting a compoundrepresented by the above general formula (IIf) to alkaline hydrolysis,and removing the protective group in the usual way as occasion demands.As the solvent used in the hydrolysis reaction, for example, methanol,ethanol, tetrahydrofuran, water, a mixed solvent thereof and the likecan be illustrated. As the base, for example, sodium hydroxide, sodiummethoxide, sodium ethoxide, methylamine, dimethylamine and the like canbe illustrated. The reaction temperature is usually from 0° C. to refluxtemperature, and the reaction time is usually from 30 minutes to 1 day,varying based on a used starting material, solvent and reactiontemperature. In case of compounds having a protective group in R¹², R²⁴,Y¹ and/or Z³ after the hydrolysis, the protective group can be suitablyremoved in the usual way as the process 1-9.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ represents a hydrogen atom; Xrepresents an oxygen atom; Y represents —CH₂CH(OH)CH₂—; and Z is R^(B),for example, can be also prepared according to the following procedures:

wherein L⁷ represents a leaving group such as a halogen atom, a mesyloxygroup, a tosyloxy group, a nosyloxy group or the like; and R^(1B), R²,R³, R⁴, R⁵, R⁶, R¹², R¹⁴, R^(B), Q, Q², T and T² have the same meaningsas defined above.Process 8-1

A compound represented by the above general formula (XXXVIII) can beprepared by subjecting a compound represented by the above generalformula (XXXVI) to O-alkylation using an alkylating agent represented bythe above general formula (XXXVII) after suitably adding a phasetransfer catalyst such as tetra(n-butyl)ammonium bromide or the like asoccasion demands in the presence of a base such as cesium carbonate,potassium carbonate, sodium hydride, sodium hydroxide, cesium fluorideor the like in an inert solvent. As the solvent used in theO-alkylation, N,N-dimethylformamide, acetone, tetrahydrofuran,chlorobenzene, dichloromethane, water, a mixed solvent thereof and thelike can be illustrated. The reaction temperature is usually from roomtemperature to reflux temperature, and the reaction time is usually from1 hour to 3 days, varying based on a used starting material, solvent andreaction temperature.

Process 8-2

An pyrazole derivative represented by the above general formula (Ih) ofthe present invention can be prepared by condensing a compoundrepresented by the above general formula (XXXVIII) with an aminecompound represented by the above general formula (XXIX) or a saltthereof in the presence or absence of a base such as triethylamine,N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]unde-7-cene,sodium hydride, potassium tert-butoxide, potassium carbonate or cesiumcarbonate in an inert solvent, subjecting the resulting compound toalkaline hydrolysis, and removing the protective group in the usual wayas occasion demands. As the solvent used in the condensing reaction, forexample, acetonitrile, N,N-dimethylformamide, methanol, ethanol,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature. As the solvent used in the hydrolysis, for example,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated. As the base, for example, sodium hydroxide,sodium methoxide, sodium ethoxide, methylamine, dimethylamine and thelike can be illustrated. The reaction temperature is usually from 0° C.to reflux temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature. In case of compounds having a protective group inR¹², R¹⁴ and/or R^(1B) after the hydrolysis, the protective group can besuitably removed in the usual way as the process 1-9.

Of the compounds represented by the above general formula (I) of thepresent invention, a compound wherein R¹ and R⁴ represents a hydrogenatom; and Z is —C(═NCN)N(R⁷)R⁸, for example, can be also preparedaccording to the following procedures:

wherein R⁷ and R⁸ are the same or different, and each represents ahydrogen atom, an aryl group which may have the same or different 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have asubstituent selected from the group consisting of a halogen atom, anamino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may havethe same or different 1 to 5 groups selected from the above substituentgroup (i), or both of R⁷ and R⁸ bind together with the neighboringnitrogen atom to form a C₂₋₆ cyclic amino group which may have asubstituent selected from the group consisting of a hydroxy group, acarbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆alkylsulfonylamino-substituted (C₁₋₆ alkyl) group; and R^(1B), R², R³,R⁵, R⁶, R¹², R¹⁴, Q, Q², T, T², X, Y and Y¹ have the same meanings asdefined above.Process 9-1

A compound represented by the above general formula (XXXX) can beprepared by condensing a compound represented by the above generalformula (IIb) with an isothioureidating reagent represented by the abovegeneral formula (XXXIX) in an inert solvent. As the solvent used in thecondensing reaction, for example, methanol, ethanol, 2-propanol,tetrahydrofuran, toluene, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature.

Process 9-2

A compound represented by the above general formula (Ii) of the presentinvention can be prepared by condensing a compound represented by theabove general formula (XXXX) with an amine compound represented by theabove general formula (XXIX) or a salt thereof in the presence orabsence of a base such as triethylamine, N,N-diisopropylethylamine,pyridine, 1,8-diazabicyclo[5.4.0]unde-7-cene, sodium hydride, potassiumtert-butoxide, potassium carbonate or cesium carbonate in an inertsolvent, subjecting the resulting compound to alkaline hydrolysis, andremoving the protective group in the usual way as occasion demands. Asthe solvent used in the condensing reaction, for example, methanol,ethanol, acetonitrile, 2-propanol, N,N-dimethylformamide,tetrahydrofuran, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temparatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature. As the solvent used in the hydrolysis, for example,methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof andthe like can be illustrated. As the base, for example, sodium hydroxide,sodium methoxide, sodium ethoxide, methylamine, dimethylamine and thelike can be illustrated. The reaction temperature is usually from 0° C.to reflux temperature, and the reaction time is usually from 30 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature. In case of compounds having a protective group inR^(1B), R¹², R¹⁴ and/or Y¹ after the hydrolysis, the protective groupcan be suitably removed in the usual way as the process 1-9.

In case of removing a protective group in the above productionprocesses, methods other than those described above can be also carriedout in the usual way.

The compounds represented by the above general formula (I) of thepresent invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography, solventextraction and solid phase extraction.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention can be converted into their pharmaceuticallyacceptable salts in the usual way. Examples of such salts include acidaddition salts with mineral acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid andthe like, acid addition salts with organic acids such as formic acid,acetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, propionic acid, citric acid, succinic acid,tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid,maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid,aspartic acid and the like, salts with inorganic bases such as a sodiumsalt, a potassium salt and the like, and salts with organic bases suchas N-methyl-D-glucamine, N,N′-dibenzyletylenediamine, 2-aminoethanol,tris(hydroxymethyl)aminomethane, arginine, lysine and the like.

The compounds represented by the above general formula (I) of thepresent invention include their solvates with pharmaceuticallyacceptable solvents such as ethanol and water.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are twogeometrical isomers in each compound having an unsaturated bond. In thepresent invention, either of cis(Z)-isomer or trans(E)-isomer can beemployed.

Of the pyrazole derivatives represented by the above general formula (I)of the present invention and the prodrugs thereof, there are two opticalisomers, R-isomer and S-isomer, in each compound having an asymmetriccarbon atom excluding the glucopyranosyloxy moiety or thegalactopyranosyloxy moiety. In the present invention, either of theisomers can be employed, and a mixture of both isomers can be alsoemployed.

A prodrug of a compound represented by the above general formula (I) ofthe present invention can be prepared by introducing an appropriategroup forming a prodrug into any one or more groups selected from ahydroxy group, an amino group and a cyclic amino group (e.g., a pyrazolering, a piperazine ring) of the compound represented by the abovegeneral formula (I) using a corresponding reagent to produce a prodrugsuch as a halide compound or the like in the usual way, and then bysuitably isolating and purificating in the usual way as occasiondemands. As a group forming a prodrug used in a hydroxy group or anamino group, for example, a C₂₋₇ acyl group, a C₁₋₆ alkoxy-substituted(C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group,a C₂₋₇ alkoxycarbonyl group, an aryl (C₂₋₇ alkoxycarbonyl) group, a C₁₋₆alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group or the like can beillustrated. As a group forming a prodrug used in a cyclic amino group,for example, a C₂₋₇ acyl group, a C₁₋₆ alkoxy-substituted (C₂₋₇ acyl)group, a C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group, a C₂₋₇alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group, a C₁₋₆alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group, a (C₂₋₇ acyloxy)methylgroup, a 1-(C₂₋₇ acyloxy)ethyl group, a (C₂₋₇ alkoxycarbonyl)-oxymethylgroup, a 1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group, a (C₃₋₇cycloalkyl)oxycarbonyloxymethyl group, a 1-[(C₃₋₇cycloalkyl)oxycarbonyloxy]ethyl group or the like can be illustrated.The term “C₁₋₆ alkoxy-substituted (C₂₋₇ acyl) group” means the aboveC₂₋₇ acyl group substituted by the above C₁₋₆ alkoxy group; the term“C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group” means the above C₂₋₇acyl group substituted by the above C₂₋₇ alkoxycarbonyl group; the term“C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group” means the aboveC₂₋₇ alkoxycarbonyl group substituted by the above C₁₋₆ alkoxy group;the term “(C₂₋₇ acyloxy)methyl group” means a hydroxymethyl groupO-substituted by the above C₂₋₇ acyl group; the term “1-(C₂₋₇acyloxy)ethyl group” means a 1-hydroxyethyl group O-substituted by theabove C₂₋₇ acyl group; the term “(C₂₋₇ alkoxycarbonyl)oxymethyl group”means a hydroxymethyl group substituted by the above C₂₋₇ alkoxycarbonylgroup; and the term “1-[(C₂₋₇ alkoxycarbonyl)oxy]ethyl group” means a1-hydroxyethyl group O-substituted by the above C₂₋₇ alkoxycarbonylgroup. In addition, the term “(C₃₋₇ cycloalkyl)oxycarbonyl group” meansa cyclic alkoxycarbonyl group having the above C₃₋₇ cycloalkyl group;the term “(C₃₋₇ cycloalkyl)oxycarbonyloxymethyl group” means ahydroxymethyl group O-substituted by the above (C₃₋₇cycloalkyl)oxycarbonyl group; and the term “1-[(C₃₋₇cycloalkyl)oxycarbonyloxy]ethyl group” means a 1-hydroxyethyl groupO-substituted by the above (C₃₋₇ cycloalkyl)oxycarbonyl group.Furthermore, as a group forming a prodrug, a glucopyranosyl group or agalactopyranosyl group can be illustrated. For example, these groups arepreferably introduced into the hydroxy group at the 4 or 6 position ofthe glucopyranosyl group or the galactopyranosyl group, and are morepreferably introduced into the hydroxy group at the 4 or 6 position ofthe glucopyranosyl group.

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, for example, showed a potent inhibitory activityin human SGLT1 in a human SGLT1 inhibitory activity confirmatory test asdescribed below, and exerted an excellent inhibitory activity of bloodglucose level increase in a confirmatory test of the inhibitory activityof blood glucose level increase in rat. Thus, the pyrazole derivativesrepresented by the above general formula (I) of the present inventionexhibit an excellent SGLT1 inhibitory activity at the small intestine,and can remarkably inhibit blood glucose level increase and/or decreaseblood galactose level by inhibiting or delaying glucose and galactoseabsorption. Therefore, a pharmaceutical composition comprising as anactive ingredient a pyrazole derivative represented by the above generalformula (I) of the present invention, a pharmaceutically acceptable saltand a prodrug thereof is extremely useful as an agent for inhibitingpostprandial hypreglycemia, an agent for the inhibition of advancingimpaired glucose tolerance (IGT) or impaired fasting glycemia (IFG) intodiabetes in a subject, and an agent for the prevention or treatment of adisease associated with hyperglycemia such as diabetes, impaired glucosetolerance, impaired fasting glycemia, diabetic complications (e.g.,retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), obesity,hyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia, gout orthe like, which relates to SGLT1 activity at the small intestine, and anagent for the prevention or treatment of a disease associated withincreasing blood galactose level such as galactosemia.

Furthermore, the compounds of the present invention can be suitably usedin combination with at least one member selected from drugs other thanSGLT2 inhibitors. Examples of the drugs which can be used in combinationwith the compounds of the present invention include an insulinsensitivity enhancer, a glucose absorption inhibitor, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, an aldose reductase inhibitor, an advanced glycationendproducts formation inhibitor, a protein kinase C inhibitor, aγ-aminobutyric acid receptor antagonist, a sodium channel antagonist, atranscript factor NF-κB inhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor (PDGF), a platelet-derivedgrowth factor (PDGF) analogue (e.g., PDGF-AA, PDGF-BB, PDGF-AB),epidermal growth factor (EGF), nerve growth factor, a carnitinederivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol,sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutarylcoenzyme A reductase inhibitor, a fibric acid derivative, aβ₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferaseinhibitor, probcol, a thyroid hormone receptor agonist, a cholesterolabsorption inhibitor, a lipase inhibitor, a microsomal triglyceridetransfer protein inhibitor, a lipoxygenase inhibitor, a carnitinepalmitoyltransferase inhibitor, a squalene synthase inhibitor, alow-density lipoprotein receptor enhancer, a nicotinic acid derivative,a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, acholesterol ester transfer protein inhibitor, an appetite suppressant,an angiotensin-converting enzyme inhibitor, a neutral endopeptidaseinhibitor, an angiotensin II receptor antagonist, anendothelin-converting enzyme inhibitor, an endothelin receptorantagonist, a diuretic agent, a calcium antagonist, a vasodilatingantihypertensive agent, a sympathetic blocking agent, a centrally actingantihypertensive agent, an α₂-adrenoceptor agonist, an antiplateletsagent, a uric acid synthesis inhibitor, a uricosuric agent and a urinaryalkalinizer.

In case of uses of the compound of the present invention in combinationwith the above one or more drugs, the present invention includes eitherdosage forms of simultaneous administration as a single preparation orseparated praparations in way of the same or different administrationroute, and administration at different dosage intervals as separatedpraparations in way of the same or different administration route. Apharmaceutical combination comprising the compound of the presentinvention and the above drug(s) includes both dosage forms as a singlepreparation and separated preparations for combination as mentionedabove.

The compounds of the present invention can obtain more advantageouseffects than additive effects in the prevention or treatment of theabove diseases when using suitably in combination with the above one ormore drugs. Also, the administration dose can be decreased in comparisonwith administration of either drug alone, or adverse effects ofcoadministrated drugs other than SGLT1 inhibitors can be avoided ordeclined.

Concrete compounds as the drugs used for combination and preferablediseases to be treated are exemplified as follows. However, the presentinvention is not limited thereto, and the concrete compounds includetheir free compounds, and their or other pharmaceutically acceptablesalts.

As insulin sensitivity enhancers, peroxisome proliferator-activatedreceptor-γ agonists such as troglitazone, pioglitazone hydrochloride,rosiglitazone maleate, sodium darglitazone, GI-262570, isaglitazone,LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929,ciglitazone, sodium englitazone and NIP-221, peroxisomeproliferator-activated receptor-α agonists such as GW-9578 andBM-170744, peroxisome proliferator-activated receptor-α/γ agonists suchas GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 andDRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204,MX-6054, AGN-194204, LG-100754 and bexarotene, and other insulinsensitivity enhancers such as reglixane, ONO-5816, MBX-102, CRE-1625,FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975,CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929,AR-H049020 and GW-501516 are illustrated. Insulin sensitivity enhancersare used preferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperinsulinemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder oratherosclerosis, and more preferably for diabetes, impaired glucosetolerance or hyperinsulinemia bacause of improving the disturbance ofinsulin signal transduction in peripheral tissues and enhancing glucoseuptake into the tissues from the blood, leading to lowering of bloodglucose level.

As glucose absorption inhibitors, compounds other othan SGLT1inhibitors, for example, α-glucosidase inhibitors such as acarbose,voglibose, miglitol, CKD-711, emiglitate, MDL-25,637, camiglibose andMDL-73,945, and α-amylase inhibitors such as AZM-127 are illustrated.Glucose absorption inhibitors are used preferably for diabetes, impairedglucose tolerance, diabetic complications, obesity or hyperinsulinemia,and more preferably for impaired glucose tolerance because of inhibitingthe gastrointestinal enzymatic digestion of carbohydrates contained infoods, and inhibiting or delaying the absorption of glucose into thebody.

As biguanides, phenformin, buformin hydrochloride, metforminhydrochloride or the like are illustrated. Biguanides are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications or hyperinsulinemia, and more preferably for diabetes,impaired glucose tolerance or hyperinsulinemia because of lowering bloodglucose level by inhibitory effects on hepatic gluconeogenesis,accelerating effects on anaerobic glycolysis in tissues or improvingeffects on insulin resistance in peripheral tissues.

As insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide,1-butyl-3-metanilylurea, carbutamide, glibornuride, glipizide,gliquidone, glisoxapide, glybuthiazol, glybuzole, glyhexamide, sodiumglymidine, glypinamide, phenbutamide, tolcyclamide, glimepiride,nateglinide, mitiglinide calcium hydrate, repaglinide or the like areillustrated. In addition, the insulin secretion enhancers includeglucokinase activators such as RO-28-1675. Insulin secretion enhancersare used preferably for diabetes, impaired glucose tolerance or diabeticcomplications, and more preferably for diabetes or impaired glucosetolerance because of lowering blood glucose level by acting onpancreatic β-cells and enhancing the insulin secretion.

As SGLT2 inhibitors, T-1095 and compounds described in Japanese patentpublications Nos. Hei10-237089 and 2001-288178, and InternationalPublications Nos. WO01/16147, WO01/27128, WO01/68660, WO01/74834,WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/53573 etc. areillustrated. SGLT2 inhibitors are used preferably for diabetes, impairedglucose tolerance, diabetic complications, obesity or hyperinsulinemia,and more preferably for diabetes, impaired glucose tolerance, obesity orhyperinsulinemia because of lowering blood glucose level by inhibitingthe reabsorption of glucose at the kidney's proximal tubule.

As insulin or insulin analogues, human insulin, animal-derived insulin,human or animal-derived insulin analogues or the like are illustrated.These preparations are used preferably for diabetes, impaired glucosetolerance or diabetic complications, and more preferably for diabetes orimpaired glucose tolerance.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687 or the likeare illustrated; as insulin receptor kinase stimulants, TER-17411,L-783281, KRX-613 or the like are illustrated; as tripeptidyl peptidaseII inhibitors, UCL-1397 or the like are illustrated; as dipeptidylpeptidase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 or the like areillustrated; as protein tyrosine phosphatase 1B inhibitors, PTP-112,OC-86839, PNU-177496 or the like are illustrated; as glycogenphosphorylase inhibitors, NN-4201, CP-368296 or the like areillustrated; as fructose-bisphosphatase inhibitors, R-132917 or the likeare illustrated; as pyruvate dehydrogenase inhibitors, AZD-7545 or thelike are illustrated; as hepatic gluconeogenesis inhibitors, FR-225659or the like are illustrated; as glucagon-like peptide-1 analogues,exendin-4, CJC-1131 or the like are illustrated; as glucagon-likepeptide 1 agonists; AZM-134, LY-315902 or the like are illustrated; andas amylin, amylin analogues or amylin agonists, pramlintide acetate orthe like are illustrated. These drugs, glucose-6-phosphatase inhibitors,D-chiroinsitol, glycogen synthase kinase-3 inhibitors and glucagon-likepeptide-1 are used preferably for diabetes, impaired glucose tolerance,diabetic complications or hyperinsulinemia, and more preferably fordiabetes or impaired glucose tolerance.

As aldose reductase inhibitors, ascorbyl gamolenate, tolrestat,epalrestat, ADN-138, BAL-AR138, ZD-5522, ADN-311, GP-1447, IDD-598,fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat,methosorbinil, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat,AS-3201, NZ-314, SG-210, JTT-811, lindolrestat or the like areillustrated. Aldose reductase inhibitors are preferably used fordiabetic complications because of inhibiting aldose reductase andlowering excessive intracellular accumulation of sorbitol in accelatedpolyol pathway which are in continuous hyperglycemic condition in thetissues in diabetic complications.

As advanced glycation endproducts formation inhibitors, pyridoxamine,OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride or the like areillustrated. Advanced glycation endproducts formation inhibitors arepreferably used for diabetic complications because of inhibitingformation of advanced glycation endproducts which are accelated incontinuous hyperglycemic condition in diabetes and declining of cellulardamage.

As protein kinase C inhibitors, LY-333531, midostaurin or the like areillustrated. Protein kinase C inhibitors are preferably used fordiabetic complications because of inhibiting of protein kinase Cactivity which is accelated in continuous hyperglycemic condition indiabetes.

As γ-aminobutyric acid receptor antagonists, topiramate or the like areillustrated; as sodium channel antagonists, mexiletine hydrochloride,oxcarbazepine or the like are illustrated; as transcrit factor NF-κBinhibitors, dexlipotam or the like are illustrated; as lipid peroxidaseinhibitors, tirilazad mesylate or the like are illustrated; asN-acetylated-α-linked-acid-dipeptidase inhibitors, GPI-5693 or the likeare illustrated; and as carnitine derivatives, carnitine,levacecaminehydrochloride, levocarnitinechloride, levocarnitine, ST-261or the like are illustrated. These drugs, insulin-like growth factor-I,platelet-derived growth factor, platelet derived growth factoranalogues, epidermal growth factor, nerve growth factor, uridine,5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide and Y-128are preferably used for diabetic complications.

As antidiarrhoics or cathartics, polycarbophil calcium, albumin tannate,bismuth subnitrate or the like are illustrated. These drugs arepreferably used for diarrhea, constipation or the like accompanyingdiabetes or the like.

As hydroxymethylglutaryl coenzyme A reductase inhibitors, sodiumcerivastatin, sodium pravastatin, lovastatin, simvastatin, sodiumfluvastatin, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101,BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987,calcium pitavastatin, calcium rosuvastatin, colestolone, dalvastatin,acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950,glenvastatin, carvastatin, BMY-22089, bervastatin or the like areillustrated. Hydroxymethylglutaryl coenzyme A reductase inhibitors areused preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypercholesterolemia oratherosclerosis because of lowering blood cholesterol level byinhibiting hydroxymethylglutaryl coenzyme A reductase.

As fibric acid derivatives, bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibricacid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate,ronifibrate, simfibrate, theofibrate, AHL-157 or the like areillustrated. Fibric acid derivatives are used preferably forhyperinsulinemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, andmore preferably for hyperlipidemia, hypertriglyceridemia oratherosclerosis because of activating hepatic lipoprotein lipase andenhancing fatty acid oxidation, leading to lowering of bloodtriglyceride level.

As β₃-adrenoceptor agonists, BRL-28410, SR-58611A, ICI-198157, ZD-2079,BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413,SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552,D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353,N-5984, GW-2696, YM178 or the like are illustrated. β₃-Adrenoceptoragonists are used preferably for obesity, hyperinsulinemia,hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipidmetabolism disorder, and more preferably for obesity or hyperinsulinemiabecause of stimulating β₃-adrenoceptor in adipose tissue and enhancingthe fatty acid oxidation, leading to induction of energy expenditure.

As acyl-coenzyme A cholesterol acyltransferase inhibitors, NTE-122,MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139,CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115,FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8-434, avasimibe,C1-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E,lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe or thelike are illustrated. Acyl-coenzyme A cholesterol acyltransferaseinhibitors are used preferably for hyperlipidemia, hypercholesterolemia,hypertriglyceridemia or lipid metabolism disorder, and more preferablyfor hyperlipidemia or hypercholesterolemia because of lowering bloodcholesterol level by inhibiting acyl-coenzyme A cholesterolacyltransferase.

As thyroid hormone recptor agonists, sodium liothyronine, sodiumlevothyroxine, KB-2611 or the like are illustrated; as cholesterolabsorption inhibitors, ezetimibe, SCH-48461 or the like are illustrated;as lipase inhibitors, orlistat, ATL-962, AZM-131, RED-103004 or the likeare illustrated; as carnitine palmitoyltransferase inhibitors, etomoxiror the like are illustrated; as squalene synthase inhibitors,SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393,ER-27856 or the like are illustrated; as nicotinic acid derivatives,nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox, nicorandilor the like are illustrated; as bile acid sequestrants, colestyramine,colestilan, colesevelam hydrochloride, GT-102-279 or the like areillustrated; as sodium/bile acid cotransporter inhibitors, 264W94,S-8921, SD-5613 or the like are illustrated; and as cholesterol estertransfer protein inhibitors, PNU-107368E, SC-795, JTT-705, CP-529414 orthe like are illustrated. These drugs, probcol, microsomal trigylceridetransfer protein inhibitors, lipoxygenase inhibitors and low-densitylipoprotein receptor enhancers are preferably used for hyperlipidemia,hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder.

As appetite suppressants, monoamine reuptake inhibitors, serotoninreuptake inhibitors, serotonin releasing stimulants, serotonin agonists(especially 5HT₂c-agonists), noradrenaline reuptake inhibitors,noradrenaline releasing stimulants, α₁-adrenoceptor agonists,β₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptorantagonists, γ-aminobutyric acid receptor antagonists, H₃-histamineantagonists, L-histidine, leptin, leptin analogues, leptin receptoragonists, melanocortin receptor agonists (especially, MC3-R agonists,MC4-R agonists), α-melanocyte stimulating hormone, cocaine- andamphetamine-regulated transcript, mahogany protein, enterostatinagonists, calcitonin, calcitonin-gene-related peptide, bombesin,cholecystokinin agonists (especially CCK-A agonists),corticotropin-releasing hormone, corticotrophin-releasing hormoneanalogues, corticotropin-releasing hormone agonists, urocortin,somatostatin, somatostatin analogues, somatostatin receptor agonists,pituitary adenylate cyclase-activatingpeptide, brain-derivedneurotrophicfactor, ciliary neurotrophic factor, thyrotropin-releasing hormone,neurotensin, sauvagine, neuropeptide Y antagonists, opioid peptideantagonists, galanin antagonists, melanin-concentrating hormoneantagonists, agouti-related protein inhibitors and orexin receptorantagonists are illustrated. Concretely, as monoamine reuptakeinhibitors, mazindol or the like are illustrated; as serotonin reuptakeinhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutraminehydrochloride, fluvoxamine maleate, sertraline hydrochloride or the likeare illustrated; as serotonin agonists, inotriptan, (+)-norfenfluramineor the like are illustrated; as noradrenaline reuptake inhibitors,bupropion, GW-320659 or the like are illustrated; as noradrenalinereleasing stimulants, rolipram, YM-992 or the like are illustrated; asβ₂-adrenoceptor agonists, amphetamine, dextroamphetamine, phentermine,benzphetamine, methamphetamine, phendimetrazine, phenmetrazine,diethylpropion, phenylpropanolamine, clobenzorex or the like areillustrated; as dopamine agonists, ER-230, doprexin, bromocriptinemesylate or the like are illustrated; as cannabinoid receptorantagonists, rimonabant or the like are illustrated; as γ-aminobutyricacid receptor antagonists, topiramate or the like are illustrated; asH₃-histamine antagonists, GT-2394 or the like are illustrated; asleptin, leptin analogues or leptin receptor agonists, LY-355101 or thelike are illustrated; as cholecystokinin agonists (especially CCK-Aagonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849,GI-248573, GW-7178, GI-181771, GW-7854, A-71378 or the like areillustrated; and as neuropeptide Y antagonists, SR-120819-A, PD-160170,NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01,J-115814 or the like are illustrated. Appetite suppressants are usedpreferably for diabetes, impaired glucose tolerance, diabeticcomplications, obesity, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, lipid metabolism disorder, atherosclerosis,hypertension, congestive heart failure, edema, hyperuricemia or gout,and more preferably for obesity because of stimulating or inhibiting theactivities of intracerebral monoamines or bioactive peptides in centralappetite regulatory system and suppressing the appetite, leading toreduction of energy intake.

As angiotensin-converting enzyme inhibitors, captopril, enalaprimaleate, alacepril, delapril hydrochloride, ramipril, lisinopril,imidapril hydrochloride, benazepril hydrochloride, ceronaprilmonohydrate, cilazapril, sodium fosinopril, perindopril erbumine,calcium moveltipril, quinapril hydrochloride, spirapril hydrochloride,temocapril hydrochloride, trandolapril, calcium zofenopril, moexiprilhydrochloride, rentiapril or the like are illustrated.Angiotensin-converting enzyme inhibitors are preferably used fordiabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240,fasidotril, sampatrilat, GW-660511×, mixanpril, SA-7060, E-4030,SLV-306, ecadotril or the like are illustrated.

Neutral endopeptidase inhibitors are preferably used for diabeticcomplications or hypertension.

As angiotensin II receptor antagonists, candesartan cilexetil,candesartan cilexetil/hydrochlorothiazide, potassium losartan,eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174,L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276,EMD-90423, BR-9701 or the like are illustrated. Angiotensin II receptorantagonists are preferably used for diabetic complications orhypertension.

As endothelin-converting enzyme inhibitors, CGS-31447, CGS-35066,SM-19712 or the like are illustrated; as endothelin receptorantagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355,PD-180988, sodiumsitaxsentan, BMS-193884, darusentan, TBC-3711,bosentan, sodium tezosentan, J-104132, YM-598, S-0139, SB-234551,RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 orthe like are illustrated. These drugs are preferably used for diabeticcomplications or hypertension, and more preferably for hypertension.

As diuretic agents, chlorthalidone, metolazone, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, methyclothiazide, indapamide,tripamide, mefruside, azosemide, etacrynic acid, torasemide, piretanide,furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone,triamterene, aminophylline, cicletanine hydrochloride, LLU-α,PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin,acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan,conivaptan hydrochloride or the like are illustrated. Diuretic drugs arepreferably used for diabetic complications, hypertension, congestiveheart failure or edema, and more preferably for hypertension, congestiveheart failure or edema because of reducing blood pressure or improvingedema by increasing urinary excretion.

As calcium antagonists, aranidipine, efonidipine hydrochloride,nicardipine hydrochloride, barnidipine hydrochloride, benidipinehydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine,nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besilate,pranidipine, lercanidipine hydrochloride, isradipine, elgodipine,azelnidipine, lacidipine, vatanidipine hydrochloride, lemildipine,diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride,S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamilhydrochloride or the like are illustrated; as vasodilatingantihypertensiveagents, indapamide, todralazinehydrochloride,hydralazine hydrochloride, cadralazine, budralazine or the like areillustrated; as sympathetic blocking agents, amosulalol hydrochloride,terazosin hydrochloride, bunazosin hydrochloride, prazosinhydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol,metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride,nebivolol, betaxolol hydrochloride, pindolol, tertatolol hydrochloride,bevantolol hydrochloride, timolol maleate, carteolol hydrochloride,bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutololsulfate, acebutolol hydrochloride, tilisolol hydrochloride, nadolol,urapidil, indoramin or the like are illustrated; as centrally actingantihypertensive agents, reserpine or the like are illustrated; and asα₂-adrenoceptor agonists, clonidine hydrochloride, methyldopa, CHF-1035,guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine,talipexole hydrochloride or the like are illustrated. These drugs arepreferably used for hypertension.

As antiplatelets agents, ticlopidine hydrochloride, dipyridamole,cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazepdihydrochloride, trapidil, beraprost sodium, aspirin or the like areillustrated. Antiplatelets agents are preferably used foratherosclerosis or congestive heart failure.

As uric acid synthesis inhibitors, allopurinol, oxypurinol or the likeare illustrated; as uricosuric agents, benzbromarone, probenecid or thelike are illustrated; and as urinary alkalinizers, sodium hydrogencarbonate, potassium citrate, sodium citrate or the like areillustrated. These drugs are preferably used for hyperuricemia or gout.

In case of uses in combination with drugs other than SGLT2 inhibitors,for example, in the use for diabetes, the combination with at least onemember of the group consisting of an insulin sensitivity enhancer, aglucose absorption inhibitor, a biguanide, an insulin secretionenhancer, a SGLT2 inhibitors, an insulin or insulin analogue, a glucagonreceptor antagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist and an appetitesuppressant is preferable; the combination with at least one member ofthe group consisting of an insulin sensitivity enhancer, a biguanide, aninsulin secretion enhancer, a SGLT2 inhibitors, an insulin or insulinanalogue, a glucagon receptor antagonist, an insulin receptor kinasestimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidaseIV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogenphosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogueand an amylin agonist is more preferable; and the combination with atleast one member of the group consisting of an insulin sensitivityenhancer, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitorand an insulin or insulin analogue is most preferable. Similarly, in theuse for diabetic complications, the combination with at least one memberof the group consisting of an insulin sensitivity enhancer, a glucoseabsorption inhibitor, a biguanide, an insulin secretion enhancer, aSGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptorantagonist, an insulin receptor kinase stimulant, a tripeptidylpeptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a proteintyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, aglucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, apyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor,D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-likepeptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1agonist, amylin, an amylin analogue, an amylin agonist, an aldosereductase inhibitor, an advanced glycation endproducts formationinhibitor, a protein kinase C inhibitor, a γ-aminobutyric acidantagonist, a sodium channel antagonist, a transcript factor NF-κBinhibitor, a lipid peroxidase inhibitor, anN-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growthfactor-I, platelet-derived growth factor, a platelet derived growthfactor analogue, epidermal growth factor, nerve growth factor, acarnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761,bimoclomol, sulodexide, Y-128, an angiotensin-converting enzymeinhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptorantagonist, an endothelin-converting enzyme inhibitor, an endothelinreceptor antagonist and a diuretic agnet is preferable; and thecombination with at least one member of the group consisting of analdose reductase inhibitor, an angiotensin-converting enzyme inhibitor,a neutral endopeptidase inhibitor and an angiotensin II receptorantagonist is more preferable. Furthermore, in the use for obesity, thecombination with at least one member of the group consisting of aninsulin sensitivity enhancer, a glucose absorption inhibitor, abiguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulinor insulin analogue, a glucagon receptor antagonist, an insulin receptorkinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, aglycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, afructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, ahepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthasekinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue,an amylin agonist, a β₃-adrenoceptor agonist and an appetite suppressantis preferable; and the combination with at least one member of the groupconsisting of a SGLT2 inhibitor, a β₃-adrenoceptor agonist and anappetite suppressant is more preferable.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry sirups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered. Thepharmaceutical compositions of the present invention also includesustained release formulation including gastrointestinal mucoadhesiveformulation (e.g., International publications Nos. WO99/10010,WO99/26606, and Japanese patent publication No. 2001-2567).

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving with an appropriate pharmaceutical additive suchas excipients, disintegrators, binders, lubricants, diluents, buffers,isotonicities, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with conventional methods. In caseof the uses of the compound of the present invention in combination withthe drug(s) other than SGLT1 inhibitors, they can be prepared byformulating each active ingredient together or individually.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I), a pharmaceuticallyacceptable salt thereof or a prodrug thereof as the active ingredient isappropriately decided depending on the age, sex, body weight and degreeof symptoms and treatment of each patient, which is approximately withinthe range of from 0.1 to 1,000 mg per day per adult human in the case oforal administration and approximately within the range of from 0.01 to300 mg per day per adult human in the case of parenteral administration,and the daily dose can be divided into one to several doses per day andadministered suitably. Also, in case of the uses of the compound of thepresent invention in combination with the drug(s) other than SGLT1inhibitors, the dosage of the compound of the present invention can bedecreased, depending on the dosage of the drug(s) other than SGLT1inhibitors.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

Reference Example 1 2-Amino-2-methylpropionamide

To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (1 g)in N,N-dimethylformamide (10 mL) were added 251-hydroxybenzotriazole(0.63 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2mL), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with 0.5mol/L hydrochloric acid, water, 1 mol/L aqueous sodium hydroxidesolution, water and brine successively, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to give2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g). This materialwas dissolved in methanol (5 mL). To the solution was added 10%palladium-carbon powder (30 mg), and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 3 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (0.11 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (6H, s), 1.9 (2H, brs), 6.83 (1H, brs),7.26 (1H, brs)

Reference Example 2 2-(2-Nitrobenzenesulfonylamino)acetoamide

To a suspension of glycinamide hydrochloride (0.11 g) and triethylamine(0.35 mL) in dichloromethane (3 mL) was added 2-nitrobenzenesulfonylchloride (0.27 g), and the mixture was stirred at room temperature for 1hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid,and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water and brine successively, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: dichloromethane/methanol=20/1) to give the titlecompound (72 mg).

H-NMR (DMSO-d₆) δ ppm: 3.57 (2H, d, J=5.9 Hz), 7.1 (1H, brs), 7.33 (1H,brs), 7.8-7.9 (2H, m), 7.95-8.1 (2H, m), 8.16 (1H, t, J=5.9 Hz)

Reference Example 3 (S)-2-(2-Nitrobenzenesulfonylamino)propionamide

The title compound was prepared in a similar manner to that described inReference Example 2 using L-alanine amide hydrochloride instead ofglycinamide hydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.33 (3H, d, J=7.1 Hz), 4.03 (1H, q, J=7.1 Hz),7.75-7.85 (2H, m), 7.85-7.9 (1H, m), 8.05-8.15 (1H, m)

Reference Example 4 2-Methyl-2-(2-nitrobenzenesulfonylamino)propionamide

The title compound was prepared in a similar manner to that described inReference Example 2 using 2-amino-2-methylpropionamide instead ofglycinamide hydrochloride.

H-NMR (DMSO-d₆) δ ppm: 1.32 (6H, s), 7.2-7.3 (2H, m), 7.8-7.9 (2H, m),7.92 (1H, s), 7.95-8.0 (1H, m), 8.05-8.15 (1H, m)

Reference Example 5 3-(2-Nitrobenzenesulfonylamino)propionamide

The title compound was prepared in a similar manner to that described inReference Example 2 using 3-aminopropionamide hydrochloride instead ofglycinamide hydrochloride.

¹H-NMR (DMSO-d₆) δ ppm: 2.27 (2H, t, J=7.3 Hz), 3.0-3.15 (2H, m), 6.85(1H, brs), 7.34 (1H, brs), 7.8-7.9 (2H, m), 7.95-8.05 (3H, m)

Reference Example 6 [4-(3-Benzyloxypropoxy)phenyl]methanol

To a solution of 4-hydroxybenzaldehyde (2.44 g) in N,N-dimethylformamide(20 mL) were added cesium carbonate (7.17 g), benzyl 3-bromopropyl ether(4.81 g) and a catalytic amount of sodium iodide, and the mixture wasstirred at room temperature for 4 days. The reaction mixture was pouredinto water, and the resulting mixture was extracted with diethyl ether.The organic layer was washed with water, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive 4-(3-benzyloxypropoxy)benzaldehyde. This material was dissolved inethanol (20 mL). To the solution was added sodium borohydride (757 mg),and the mixture was stirred at room temperature for 3 hours. To thereaction mixture was added methanol, and the resulting mixture wasconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with diethyl ether. The organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=5/1-2/1) to give the titlecompound (5.17 g).

H-NMR (CDCl₃) δ ppm: 1.54 (1H, t, J=5.9 Hz), 2.05-2.15 (2H, m), 3.66(2H, t, J=6.2 Hz), 4.09 (2H, t, J=6.2 Hz), 4.52 (2H, s), 4.61 (2H, d.J=5.9 Hz), 6.85-6.95 (2H, m), 7.2-7.35 (7H, m)

Reference Example 7 [4-(2-Benzyloxyethoxy)phenyl]methanol

The title compound was prepared in a similar manner to that described inReference Example 6 using benzyl 2-bromoethyl ether instead of benzyl3-bromopropyl ether.

¹H-NMR (CDCl₃) δ ppm: 1.53 (1H, t, J=5.8 Hz), 3.8-3.85 (2H, m), 4.1-4.2(2H, m), 4.62 (2H, d, J=5.8 Hz), 4.64 (2H, s), 6.85-6.95 (2H, m),7.25-7.4 (7H, m)

Reference Example 8 [4-(4-Benzyloxybutoxy)phenyl]methanol

The title compound was prepared in a similar manner to that described inReference Example 6 using benzyl 4-bromobutyl ether instead of benzyl3-bromopropyl ether.

H-NMR (CDCl₃) δ ppm: 1.52 (1H, t, J=5.6 Hz), 1.75-1.95 (4H, m), 3.54(2H, t, J=6.1 Hz), 3.98 (2H, t, J=6.3 Hz), 4.52 (2H, s), 4.61 (2H, d,J=5.6 Hz), 6.8-6.9 (2H, m), 7.2-7.4 (7H, m)

Reference Example 9 [4-(3-Benzyloxypropoxy)-2-methylphenyl]methanol

To a solution of 4-bromo-3-methylphenol (2.5 g) in N,N-dimethylformamide(10 mL) were added cesium carbonate (4.79 g), benzyl 3-bromopropyl ether(2.48 mL) and a catalytic amount of sodium iodide, and the mixture wasstirred at room temperature for 60 hours. The reaction mixture waspoured into water, and the resulting mixture was extracted with diethylether. The organic layer was washed with water, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive 4-(3-benzyloxypropoxy)-1-bromo-2-methylbenzene. This material wasdissolved in tetrahydrofuran (100 mL). To the solution was added n-butyllithium (2.46 mol/L n-hexane solution, 6 mL) at −78° C. under an argonatmosphere, and the mixture was stirred for 5 minutes. To the reactionmixture was added N,N-dimethylformamide (2.57 mL), and the mixture wasallowed to warm to 0° C. and stirred for 1 hour. The reaction mixturewas poured into water, and the resulting mixture was extracted withdiethyl ether. The organic layer was washed with water and brinesuccessively, and dried over anhydrous magnesium sulfate. The solventwas removed under reduced pressure to give4-(3-benzyloxypropoxy)-2-methylbenzaldehyde. This material was dissolvedin ethanol (40 mL). To the solution was added sodium borohydride (506mg), and the mixture was stirred at room temperature overnight. To thereaction mixture was added methanol, and the resulting mixture wasconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with diethyl ether. The organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=5/1-1.5/1) to give thetitle compound (3.33 g).

¹H-NMR (CDCl₃) δ ppm: 1.37 (1H, t, J=5.7 Hz), 2.0-2.15 (2H, m), 2.36(3H, s), 3.66 (2H, t, J=6.2 Hz), 4.08 (2H, t, J=6.3 Hz), 4.52 (2H, s),4.63 (2H, d, J=5.7 Hz), 6.65-6.8 (2H, m), 7.15-7.4 (6H, m)

Reference Example 10 [4-(2-Benzyloxyethoxy)-2-methylphenyl]methanol

The title compound was prepared in a similar manner to that described inReference Example 9 using benzyl 2-bromoethyl ether instead of benzyl3-bromopropyl ether.

¹H-NMR (CDCl₃) δ ppm: 1.39 (1H, t, J=5.8 Hz), 2.35 (3H, s), 3.8-3.85(2H, m), 4.1-4.2 (2H, m), 4.6-4.65 (4H, m), 6.73 (1H, dd, J=8.2 Hz, 2.6Hz), 6.78 (1H, d, J=2.6 Hz), 7.22 (1H, d, J=8.2 Hz), 7.25-7.4 (5H, m)

Reference Example 114-{[4-(3-Benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of [4-(3-benzyloxypropoxy)phenyl]methanol (5.17 g) intetrahydrofuran (25 mL) were added triethylamine (3.04 mL) andmethanesulfonyl chloride (1.62 mL) under ice-cooling, and the mixturewas stirred for 1 hour. The insoluble material was removed byfiltration. The obtained solution of[4-(3-benzyloxypropoxy)phenyl]methyl mesylate in tetrahydrofuran wasadded to a suspension of sodium hydride (60%, 875 mg) and ethyl4-methyl-3-oxopentanoate (3.3 g) in tetrahydrofuran (50 mL), and themixture was heated for reflux for 8 hours. To the reaction mixture wasadded 1 mol/L hydrochloric acid, and the resulting mixture was extractedwith diethyl ether. The organic layer was washed with water, and driedover an hydrous magnesium sulfate. The solvent was removed under reducedpressure. To a solution of the residue in toluene (10 mL) was addedhydrazine monohydrate (2.76 mL), and the mixture was stirred at 100° C.overnight. The reaction mixture was purified by column chromatography onsilica gel (eluent: dichloromethane/methanol=50/1-20/1) to give thetitle compound (5.22 g).

¹H-NMR (CDCl₃) δ ppm: 1.14 (6H, d, J=6.8 Hz), 2.0-2.1 (2H, m), 2.8-2.95(1H, m), 3.6-3.7 (4H, m), 4.04 (2H, t, J=6.5 Hz), 4.51 (2H, s),6.75-6.85 (2H, m), 7.05-7.15 (2H, m), 7.2-7.35 (5H, m)

Reference Example 124-{[4-(2-Benzyloxyethoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using [4-(2-benzyloxyethoxy)phenyl]methanol insteadof [4-(3-benzyloxypropoxy)-phenyl]methanol.

¹H-NMR (CDCl₃) δ ppm: 1.14 (6H, d, J=7.3 Hz), 2.8-2.95 (1H, m), 3.66(2H, s), 3.75-3.85 (2H, m), 4.05-4.15 (2H, m), 4.62 (2H, s), 6.75-6.85(2H, m), 7.1-7.15 (2H, m), 7.25-7.4 (5H, m)

Reference Example 134-{[4-(4-Benzyloxybutoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using [4-(4-benzyloxybutoxy)phenyl]methanol insteadof [4-(3-benzyloxypropoxy)-phenyl]methanol.

¹H-NMR (CDCl₃) δ ppm: 1.14 (6H, d, J=7.0 Hz), 1.7-1.9 (4H, m), 2.8-2.95(1H, m), 3.53 (2H, t, J=6.1 Hz), 3.66 (2H, s), 3.93 (2H, t, J=6.3 Hz),4.51 (2H, s), 6.7-6.8 (2H, m), 7.05-7.15 (2H, m), 7.2-7.35 (5H, m)

Reference Example 144-{[4-(3-Benzyloxypropoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using[4-(3-benzyloxypropoxy)-2-methylphenyl]methanol instead of[4-(3-benzyloxypropoxy)phenyl]methanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (6H, d, J=7.0 Hz), 1.9-2.0 (2H, m), 2.24(3H, s), 2.65-2.8 (1H, m), 3.44 (2H, s), 3.56 (2H, t, J=6.4 Hz), 3.97(2H, t, J=6.1 Hz), 4.47 (2H, s), 6.6 (1H, dd, J=8.6 Hz, 2.6 Hz), 6.69(1H, d, J=2.6 Hz), 6.78 (1H, d, J=8.6 Hz), 7.2-7.35 (5H, m)

Reference Example 154-[(4-Benzyloxyphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using (4-benzyloxyphenyl)methanol instead of[4-(3-benzyloxypropoxy)phenyl]-methanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.06 (6H, d, J=6.8 Hz), 2.75-2.9 (1H, m), 3.5(2H, s), 5.03 (2H, s), 6.85-6.9 (2H, m), 7.0-7.1 (2H, m), 7.25-7.45 (5H,m)

Reference Example 164-{[4-(2-Benzyloxyethoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using[4-(2-benzyloxypropoxy)-2-methylphenyl]methanol instead of[4-(3-benzyloxypropoxy)phenyl]methanol.

¹H-NMR (CDCl₃) δ ppm: 1.1 (6H, d, J=6.9 Hz), 2.3 (3H, s), 2.75-2.9 (1H,m), 3.6 (2H, s), 3.75-3.85 (2H, m), 4.05-4.15 (2H, m), 4.62 (2H, s),6.64 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.74 (1H, d, J=2.5 Hz), 6.94 (1H, d,J=8.5 Hz), 7.25-7.4 (5H, m)

Reference Example 173-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of4-{[4-(3-benzyloxypropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one(5.08 g), acetobromo-α-D-glucose (5.49 g) and benzyltri(n-butyl)ammoniumchloride (2.08 g) in dichloromethane (40 mL) was added 5 mol/L aqueoussodium hydroxide solution (8 mL), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was purified by columnchromatography on aminopropylated silica gel (eluent: n-hexane/ethylacetate=1/1-1/3-1/5). The purified material was further purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=1/1-1/2-1/4) to give the title compound (2.75 g).

¹H-NMR (CDCl₃) δ ppm: 1.15 (6H, d, J=7.1 Hz), 1.87 (3H, s), 1.95-2.1(11H, m), 2.85-2.95 (1H, m), 3.5-3.7 (4H, m), 3.8-3.9 (1H, m), 4.03 (2H,t, J=6.4 Hz), 4.15 (1H, dd, J=12.3 Hz, 2.4 Hz), 4.31 (1H, dd, J=12.3 Hz,4.1 Hz), 4.51 (2H, s), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m), 6.7-6.8 (2H,m), 7.0-7.05 (2H, m), 7.2-7.35 (5H, m)

Reference Example 183-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(2-benzyloxyethoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.14 (6H, d, J=6.8 Hz), 1.88 (3H, s), 2.01 (3H,s), 2.03 (3H, s), 2.06 (3H, s), 2.8-2.95 (1H, m), 3.57 (1H, d, J=15.8Hz), 3.63 (1H, d, J=15.8 Hz), 3.75-3.9 (3H, m), 4.05-4.2 (3H, m), 4.31(1H, dd, J=12.4 Hz, 4.1 Hz), 4.62 (2H, s), 5.15-5.3 (3H, m), 5.55-5.6(1H, m), 6.75-6.85 (2H, m), 7.0-7.05 (2H, m), 7.25-7.4 (5H, m)

Reference Example 193-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-benzyloxybutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(4-benzyloxybutoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

H-NMR (CDCl₃) δ ppm: 1.15 (6H, d, J=6.7 Hz), 1.7-1.9 (7H, m), 2.01 (3H,s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.5-3.6 (3H, m), 3.62(1H, d, J=16.3 Hz), 3.8-3.9 (1H, m), 3.92 (2H, t, J=6.5 Hz), 4.1-4.2(1H, m), 4.31 (1H, dd, J=12.3 Hz, 4.1 Hz), 4.51 (2H, s), 5.15-5.3 (3H,m), 5.55-5.65 (1H, m), 6.7-6.8 (2H, m), 6.95-7.05 (2H, m), 7.2-7.4 (5H,m)

Reference Example 203-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.8 (3H, s), 1.9-2.15 (11H, m),2.25 (3H, s), 2.75-2.85 (1H, m), 3.49 (1H, d, J=16.4 Hz), 3.59 (1H, d,J=16.4 Hz), 3.64 (2H, t, J=6.3 Hz), 3.8-3.9 (1H, m), 4.0-4.05 (2H, m),4.1-4.15 (1H, m), 4.3 (1H, dd, J=12.2 Hz, 4.1 Hz), 4.51 (2H, s),5.15-5.3 (3H, m), 5.55 (1H, d, J=7.8 Hz), 6.57 (1H, dd, J=8.4 Hz, 2.6Hz), 6.68 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.4 Hz), 7.2-7.4 (5H, m)

Reference Example 213-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-benzyloxyphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-benzyloxyphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=7.1 Hz), 1.85 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.57 (1H, d, J=15.9 Hz),3.63 (1H, d, J=15.9 Hz), 3.8-3.9 (1H, m), 4.1-4.2 (1H, m), 4.31 (1H, dd,J=12.6 Hz, 3.9 Hz), 5.02 (2H, s), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m),6.8-6.9 (2H, m), 7.0-7.1 (2H, m), 7.25-7.45 (5H, m)

Reference Example 223-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(2-benzyloxyethoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.81 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.25 (3H, s), 2.7-2.85 (1H, m), 3.5 (1H, d,J=16.6 Hz), 3.59 (1H, d, J=16.6 Hz), 3.75-3.9 (3H, m), 4.05-4.2 (3H, m),4.3 (1H, dd, J=12.2 Hz, 4.1 Hz), 4.62 (2H, s), 5.1-5.3 (3H, m), 5.55(1H, d, J=8.0 Hz), 6.6 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5Hz), 6.8 (1H, d, J=8.5 Hz), 7.25-7.4 (5H, m)

Reference Example 233-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(2.75 g) was dissolved in a mixed solvent of methanol (20 mL) andtetrahydrofuran (9 mL). To the solution was added 10% palladium-carbonpowder (550 mg), and the mixture was stirred at room temperature under ahydrogen atmosphere for 4 hours. The insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure to give the title compound (2.4 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.89 (3H, s), 1.95-2.1 (11H, m),2.85-2.95 (1H, m), 3.58 (1H, d, J=16.3 Hz), 3.63 (1H, d, J=16.3 Hz),3.8-3.9 (3H, m), 4.05-4.1 (2H, m), 4.13 (1H, dd, J=12.1 Hz, 2.1 Hz), 4.3(1H, dd, J=12.1 Hz, 4.1 Hz), 5.15-5.3 (3H, m), 5.58 (1H, d, J=7.3 Hz),6.7-6.8 (2H, m), 7.0-7.05 (2H, m)

Reference Example 243-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=6.8 Hz), 1.89 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.58 (1H, d, J=16.0 Hz),3.63 (1H, d, J=16.0 Hz), 3.8-3.9 (1H, m), 3.9-4.0 (2H, m), 4.0-4.1 (2H,m), 4.1-4.2 (1H, m), 4.25-4.35 (1H, m), 5.15-5.3 (3H, m), 5.55-5.65 (1H,m), 6.75-6.85 (2H, m), 7.0-7.1 (2H, m)

Reference Example 253-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-hydroxybutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-benzyloxybutoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.65-1.8 (2H, m), 1.8-1.95 (5H,m), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.57(1H, d, J=16.2 Hz), 3.63 (1H, d, J=16.2 Hz), 3.71 (2H, t, J=6.3 Hz),3.8-3.9 (1H, m), 3.96 (2H, t, J=6.2 Hz), 4.14 (1H, dd, J=12.4 Hz, 2.4Hz), 4.31 (1H, dd, J=12.4 Hz, 4.1 Hz), 5.15-5.3 (3H, m), 5.55-5.65 (1H,m), 6.7-6.8 (2H, m), 7.0-7.05 (2H, m)

Reference Example 263-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 1.95-2.1 (11H, m),2.26 (3H, s), 2.75-2.9 (1H, m), 3.5 (1H, d, J=16.5 Hz), 3.58 (1H, d,J=16.5 Hz), 3.75-3.9 (3H, m), 4.0-4.15 (3H, m), 4.28 (1H, dd, J=12.3 Hz,4.1 Hz), 5.1-5.3 (3H, m), 5.55 (1H, d, J=7.9 Hz), 6.59 (1H, dd, J=8.3Hz, 2.5 Hz), 6.69 (1H, d, J=2.5 Hz), 6.81 (1H, d, J=8.3 Hz)

Reference Example 273-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-benzyloxyphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.89 (3H, s), 2.0 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.85-3.0 (1H, m), 3.57 (1H, d, J=16.2 Hz), 3.61(1H, d, J=16.2 Hz), 3.8-3.9 (1H, m), 4.05-4.2 (1H, m), 4.29 (1H, dd,J=12.5 Hz, 4.0 Hz), 4.91 (1H, brs), 5.15-5.3 (3H, m), 5.55-5.6 (1H, m),6.65-6.75 (2H, m), 6.95-7.05 (2H, m)

Reference Example 283-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.26 (3H, s), 2.75-2.9 (1H, m), 3.51 (1H, d,J=16.9 Hz), 3.59 (1H, d, J=16.9 Hz), 3.8-3.85 (1H, m), 3.9-3.95 (2H, m),4.0-4.1 (2H, m), 4.11 (1H, dd, J=12.5 Hz, 2.5 Hz), 4.28 (1H, dd, J=12.5Hz, 4.1 Hz), 5.1-5.3 (3H, m), 5.55 (1H, d, J=7.9 Hz), 6.6 (1H, dd, J=8.3Hz, 2.7 Hz), 6.71 (1H, d, J=2.7 Hz), 6.82 (1H, d, J=8.3 Hz)

Reference Example 293-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(2.21 g) in dichloromethane (35 mL) were added triethylamine (0.65 mL)and methanesulfonyl chloride (0.33 mL), and the mixture was stirred atroom temperature overnight. The reaction mixture was poured into 0.5mol/L hydrochloric acid, and the resulting mixture was extracted withethylacetate. The organic layer was washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)-propoxy]phenyl}methyl)-1H-pyrazole.This material was dissolved in N,N-dimethylformamide (20 mL). To thesolution was added sodium azide (0.46 g), and the mixture was stirred at100° C. for 1.5 hours. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water three times, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/1-1/3) to give the title compound (1.6 g).

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.89 (3H, s), 1.95-2.1 (11H, m),2.85-2.95 (1H, m), 3.5 (2H, t, J=6.7 Hz), 3.57 (1H, d, J=15.9 Hz), 3.63(1H, d, J=15.9 Hz), 3.8-3.9 (1H, m), 4.0 (2H, t, J=5.9 Hz), 4.1-4.2 (1H,m), 4.31 (1H, dd, J=12.2 Hz, 4.2 Hz), 5.15-5.3 (3H, m), 5.55-5.65 (1H,m), 6.7-6.8 (2H, m), 7.0-7.1 (2H, m)

Reference Example 303-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 29 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.89 (3H, s), 2.01 (3H, s), 2.03(3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.5-3.7 (4H, m), 3.8-3.9 (1H,m), 4.11 (2H, t, J=5.1 Hz), 4.14 (1H, dd, J=12.2 Hz, 2.2 Hz), 4.31 (1H,dd, J=12.2 Hz, 4.0 Hz), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m), 6.75-6.85(2H, m), 7.0-7.1 (2H, m)

Reference Example 313-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-azidobutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 29 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-hydroxybutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.7-1.95 (7H, m), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.35 (2H, t, J=6.8 Hz),3.57 (1H, d, J=16.0 Hz), 3.63 (1H, d, J=16.0 Hz), 3.8-3.9 (1H, m), 3.94(2H, t, J=6.0 Hz), 4.14 (1H, dd, J=12.6 Hz, 2.5 Hz), 4.31 (1H, dd,J=12.6 Hz, 4.1 Hz), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m), 6.7-6.8 (2H,m), 7.0-7.1 (2H, m)

Reference Example 323-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 29 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.81 (3H, s), 1.95-2.1 (11H,m), 2.26 (3H, s), 2.75-2.9 (1H, m), 3.45-3.55 (3H, m), 3.59 (1H, d,J=16.5 Hz), 3.8-3.9 (1H, m), 3.95-4.05 (2H, m), 4.05-4.15 (1H, m), 4.29(1H, dd, J=12.6 Hz, 4.1 Hz), 5.1-5.3 (3H, m), 5.55 (1H, d, J=7.9 Hz),6.57 (1H, dd, J=8.7 Hz, 2.6 Hz), 6.68 (1H, d, J=2.6 Hz), 6.8 (1H, d,J=8.7 Hz)

Reference Example 333-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 29 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.82 (3H, s), 2.0 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.27 (3H, s), 2.75-2.9 (1H, m), 3.45-3.65 (4H,m), 3.8-3.9 (1H, m), 4.05-4.15 (3H, m), 4.29 (1H, dd, J=12.2 Hz, 4.2Hz), 5.1-5.3 (3H, m), 5.56 (1H, d, J=7.7 Hz), 6.6 (1H, dd, J=8.3 Hz, 2.6Hz), 6.71 (1H, d, J=2.6 Hz), 6.82 (1H, d, J=8.3 Hz)

Example 13-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(1.6 g) in tetrahydrofuran (25 mL) was added 10% palladium-carbon powder(300 mg), and the mixture was stirred at room temperature under ahydrogen atmosphere for 2 hours. The insoluble material was removed byfiltration, and the solvent of the filtrate was removed under reducedpressure to give the title compound (1.5 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.85-2.0 (8H, m), 2.01 (3H, s),2.02 (3H, s), 2.8-3.0 (3H, m), 3.6 (2H, s), 3.9-4.0 (1H, m), 4.01 (2H,t, J=6.0 Hz), 4.11 (1H, dd, J=12.4 Hz, 2.5 Hz), 4.29 (1H, dd, J=12.4 Hz,3.9 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48 (1H, d, J=8.2 Hz),6.75-6.85 (2H, m), 7.0-7.05 (2H, m)

Example 23-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.01 (3H,s), 2.03 (3H, s), 2.06 (3H, s), 2.85-2.95 (1H, m), 3.05 (2H, t, J=5.0Hz), 3.57 (1H, d, J=16.0 Hz), 3.63 (1H, d, J=16.0 Hz), 3.8-3.9 (1H, m),3.94 (2H, t, J=5.0 Hz), 4.1-4.2 (1H, m), 4.25-4.35 (1H, m), 5.15-5.3(3H, m), 5.5-5.65 (1H, m), 6.75-6.8 (2H, m), 7.0-7.1 (2H, m)

Example 33-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-aminobutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(4-azidobutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.15 (6H, d, J=6.8 Hz), 1.5-1.65 (2H, m), 1.7-1.85(2H, m), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.76(2H, t, J=7.1 Hz), 2.85-2.95 (1H, m), 3.56 (1H, d, J=15.7 Hz), 3.62 (1H,d, J=15.7 Hz), 3.8-3.9 (1H, m), 3.92 (2H, t, J=6.5 Hz), 4.1-4.2 (1H, m),4.31 (1H, dd, J=12.2 Hz, 4.1 Hz), 5.15-5.3 (3H, m), 5.55-5.65 (1H, m),6.7-6.8 (2H, m), 6.95-7.05 (2H, m)

Example 43-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.82 (3H, s), 1.85-1.95 (2H,m), 1.99 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.25 (3H, s), 2.75-2.95(3H, m), 3.5 (1H, d, J=16.5 Hz), 3.58 (1H, d, J=16.5 Hz), 3.75-3.9 (1H,m), 3.9-4.05 (2H, m), 4.05-4.2 (1H, m), 4.29 (1H, dd, J=12.6 Hz, 4.0Hz), 5.1-5.3 (3H, m), 5.5-5.6 (1H, m), 6.58 (1H, dd, J=8.4 Hz, 2.7 Hz),6.68 (1H, d, J=2.7 Hz), 6.8 (1H, d, J=8.4 Hz)

Example 53-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.82 (3H, s), 2.0 (3H, s), 2.02(3H, s), 2.06 (3H, s), 2.26 (3H, s), 2.75-2.85 (1H, m), 3.0-3.1 (2H, m),3.5 (1H, d, J=16.3 Hz), 3.59 (1H, d, J=16.3 Hz), 3.8-3.9 (1H, m),3.9-4.0 (2H, m), 4.12 (1H, dd, J=12.4 Hz, 2.4 Hz), 4.29 (1H, dd, J=12.4Hz, 4.0 Hz), 5.15-5.3 (3H, m), 5.55 (1H, d, J=7.9 Hz), 6.59 (1H, dd,J=8.5 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6 Hz), 6.81 (1H, d, J=8.5 Hz)

Example 64-{[4-(3-Aminopropoxy)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.1 g) in methanol (2 mL) was added sodium methoxide (28% methanolsolution, 0.062 mL), and the mixture was stirred at room temperature for30 minutes. The reaction mixture was concentrated under reducedpressure, and the residue was purified by solid phase extraction on ODS(washing solvent: distilled water, eluent: methanol) to give the titlecompound (57 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.8-1.95 (2H, m), 2.8 (2H, t,J=7.0 Hz), 2.85-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.8 (3H, m),3.8-3.9 (1H, m), 3.99 (2H, t, J=6.0 Hz), 5.0-5.1 (1H, m), 6.7-6.85 (2H,m), 7.05-7.15 (2H, m)

Example 74-{[4-(2-Aminoethoxy)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-phenyl]methyl)-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.8-2.95 (1H, m), 2.96 (2H, t,J=5.4 Hz), 3.25-3.45 (4H, m), 3.6-3.7 (2H, m), 3.73 (1H, d, J=15.9 Hz),3.8-3.9 (1H, m), 3.95 (2H, t, J=5.4 Hz), 5.05-5.1 (1H, m), 6.75-6.85(2H, m), 7.05-7.15 (2H, m)

Example 84-{[4-(4-Aminobutoxy)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-=55[4-(4-aminobutoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.55-1.7 (2H, m), 1.7-1.85 (2H,m), 2.67 (2H, t, J=7.1 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.7(2H, m), 3.73 (1H, d, J=15.7 Hz), 3.8-3.9 (1H, m), 3.93 (2H, t, J=6.3Hz), 5.0-5.15 (1H, m), 6.7-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 94-{[4-(3-Aminopropoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.7-2.9 (3H, m), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H,m), 4.0 (2H, t, J=5.9 Hz), 4.95-5.1 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5Hz), 6.71 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 103-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonylamino)propoxy]phenyl}methyl)-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.36 g) in dichloromethane (6 mL) were added triethylamine (0.2 mL) andmethanesulfonyl chloride (0.05 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted withethylacetate. The organic layer was washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=1/3-ethyl acetate) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonylamino)-propoxy]phenyl}methyl)-1H-pyrazole(255 mg). This material was dissolved in methanol (6 mL). To thesolution was added sodium methoxide (28% methanol solution, 0.11 mL),and the mixture was stirred at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by solid phase extraction on ODS (washing solvent: distilledwater, eluent: methanol) to give the title compound (0.16 g).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.05 (2H, m), 2.8-2.95 (4H,m), 3.24 (2H, t, J=7.0 Hz), 3.3-3.45 (4H, m), 3.6-3.7 (2H, m), 3.73 (1H,d, J=16.0 Hz), 3.8-3.9 (1H, m), 4.01 (2H, t, J=6.1 Hz), 5.0-5.15 (1H,m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 113-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[2-(methanesulfonylamino)ethoxy]phenyl}methyl)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 10 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.8-2.95 (1H, m), 2.97 (3H, s),3.25-3.45 (6H, m), 3.6-3.7 (2H, m), 3.74 (1H, d, J=15.9 Hz), 3.8-3.9(1H, m), 4.03 (2H, t, J=5.4 Hz), 5.0-5.15 (1H, m), 6.8-6.85 (2H, m),7.05-7.15 (2H, m)

Example 124-[(4-{3-[N-(Carbamoylmethyl)-N-(methanesulfonyl)amino]-propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 10 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(carbamoylmethylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.95-2.1 (2H, m), 2.29 (3H, s),2.75-2.85 (1H, m), 3.0 (3H, s), 3.25-3.4 (4H, m), 3.46 (2H, t, J=7.1Hz), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 3.95-4.05 (4H, m), 4.95-5.05(1H, m), 6.62 (1H, dd, J=8.3 Hz, 2.7 Hz), 6.72 (1H, d, J=2.7 Hz), 6.85(1H, d, J=8.3 Hz)

Example 134-({4-[3-(2-Aminoacetylamino)propoxy]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.1 g) in N,N-dimethylformamide (1 mL) were added2-benzyloxycarbonylaminoacetic acid (51 mg), 1-hydroxybenzotriazole (33mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (93mg), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with water, asaturated aqueous sodium hydrogen carbonate solution, water and brinesuccessively, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: ethylacetate-dichloromethane/methanol=30/1-20/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-(benzyloxycarbonylamino)acetylamino]propoxy}phenyl)-methyl]-5-isopropyl-1H-pyrazole(46 mg). This material was dissolved in methanol (3 mL). To the solutionwas added 10% palladium-carbon powder (20 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 1.5 hours.The insoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(2-aminoacetylamino)propoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole(34 mg). This material was dissolved in methanol (3 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.01 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by solid phase extraction on ODS (washing solvent: distilledwater, eluent: methanol) to give the title compound (23 mg).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.9-2.0 (2H, m), 2.85-2.95 (1H,m), 3.23 (2H, s), 3.25-3.45 (6H, m), 3.6-3.7 (2H, m), 3.73 (1H, d,J=16.0 Hz), 3.8-3.9 (1H, m), 3.98 (2H, t, J=6.1 Hz), 5.0-5.1 (1H, m),6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 144-[(4-{3-[(S)-2-Aminopropionylamino]propoxy}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using (S)-2-(benzyloxycarbonylamino)propionic acid instead of2-benzyloxycarbonylaminoacetic acid.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.24 (3H, d, J=6.9 Hz), 1.9-2.0(2H, m), 2.8-2.95 (1H, m), 3.25-3.45 (7H, m), 3.6-3.8 (3H, m), 3.8-3.9(1H, m), 3.98 (2H, t, J=6.0 Hz), 5.0-5.15 (1H, m), 6.75-6.85 (2H, m),7.0-7.15 (2H, m)

Example 154-({4-[3-(3-Aminopropionylamino)propoxy]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using 3-(benzyloxycarbonylamino)propionic acid instead of2-benzyloxycarbonylaminoacetic acid.

H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-2.0 (2H, m), 2.33 (2H, t,J=6.6 Hz), 2.75-2.95 (3H, m), 3.25-3.45 (6H, m), 3.6-3.7 (2H, m), 3.73(1H, d, J=16.0 Hz), 3.8-3.9 (1H, m), 3.97 (2H, t, J=6.0 Hz), 5.0-5.1(1H, m), 6.7-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 164-[(4-{3-[(S)-2-Amino-3-hydroxypropionylamino]propoxy}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using (S)-2-benzyloxycarbonylamino-3-hydroxypropionic acidinstead of 2-benzyloxycarbonylaminoacetic acid.

H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.9-2.0 (2H, m), 2.8-2.95 (1H,m), 3.25-3.45 (7H, m), 3.55-3.7 (4H, m), 3.73 (1H, d, J=15.6 Hz),3.8-3.9 (1H, m), 3.99 (2H, t, J=6.2 Hz), 5.0-5.15 (1H, m), 6.75-6.85(2H, m), 7.05-7.15 (2H, m)

Example 174-[(4-{3-[(S)-2-Amino-3-(1H-imidazol-4-yl)propionylamino]-propoxy}phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using(S)-2-benzyloxycarbonylamino-3-(1H-imidazol-4-yl)propionic acid insteadof 2-benzyloxycarbonylaminoacetic acid.

H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.8-1.95 (2H, m), 2.7-3.0 (3H, m),3.25-3.45 (6H, m), 3.5-3.55 (1H, m), 3.6-3.7 (2H, m), 3.73 (1H, d,J=15.7 Hz), 3.8-3.95 (3H, m), 5.0-5.15 (1H, m), 6.75-6.85 (3H, m),7.05-7.15 (2H, m), 7.54 (1H, s)

Example 184-[(4-{3-[2-Amino-2-(methyl)propionylamino]propoxy}phenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using 2-benzyloxycarbonylamino-2-methylpropionic acid insteadof 2-benzyloxycarbonylaminoacetic acid.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.29 (6H, s), 1.9-2.0 (2H, m),2.8-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.7 (2H, m), 3.73 (1H, d,J=16.1 Hz), 3.8-3.9 (1H, m), 3.98 (2H, t, J=6.1 Hz), 5.0-5.15 (1H, m),6.75-6.85 (2H, m), 7.05-7.2 (2H, m)

Example 193-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[2-(morpholin-4-yl)ethyl]ureido}propoxy)phenyl]methyl}-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(97 mg) in dichloromethane (3 mL) were added triethylamine (0.035 mL)and 4-nitrophenyl chloroformate (35 mg), and the mixture was stirred atroom temperature for 1 hour. To the reaction mixture was added4-(2-aminoethyl)morpholine (41 mg), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water, a saturated aqueous sodium hydrogencarbonate solution, water and brine successively, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (eluent: ethylacetate-dichloromethane/methanol=10/1-5/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[2-(morpholin-4-yl)ethyl]ureido}propoxy)phenyl]-methyl}-1H-pyrazole(58 mg). This material was dissolved in methanol (3 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.03 mL), and themixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by solid phase extraction on ODS (washing solvent: distilledwater, eluent: methanol) to give the title compound (39 mg).

¹H-NMR (CD₃OD) δ ppm: 1.10-1.15 (6H, m), 1.85-1.95 (2H, m), 2.35-2.5(6H, m), 2.85-2.95 (1H, m), 3.2-3.45 (8H, m), 3.6-3.7 (6H, m), 3.73 (1H,d, J=15.9 Hz), 3.8-3.9 (1H, m), 3.97 (2H, t, J=6.2 Hz), 5.0-5.1 (1H, m),6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 203-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[2-(dimethylamino)ethyl]ureido}propoxy)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using N,N-dimethylethylenediamine instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.85-1.95 (2H, m), 2.26 (6H, s),2.43 (2H, t, J=6.7 Hz), 2.85-2.95 (1H, m), 3.2-3.4 (8H, m), 3.6-3.7 (2H,m), 3.73 (1H, d, J=15.9 Hz), 3.8-3.9 (1H, m), 3.97 (2H, t, J=6.0 Hz),5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 213-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethyl]ureido}propoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using 2-amino-2-methyl-1,3-propanediol instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (9H, m), 1.8-1.95 (2H, m), 2.8-2.95 (1H,m), 3.2-3.45 (6H, m), 3.5-3.8 (7H, m), 3.8-3.9 (1H, m), 3.97 (2H, t,J=6.1 Hz), 5.0-5.15 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 223-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1-(hydroxymethyl)ethyl]ureido}propoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using 2-amino-1,3-propanediol instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.8-2.95(1H, m), 3.25-3.45 (6H, m), 3.5-3.75 (8H, m), 3.8-3.9 (1H, m), 3.97 (2H,t, J=6.2 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 233-(β-D-Glucopyranosyloxy)-4-[(4-{3-[3-(2-hydroxyethyl)-ureido]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using 2-aminoethanol instead of 4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-1.95 (2H, m), 2.85-2.95(1H, m), 3.21 (2H, t, J=5.6 Hz), 3.25-3.45 (6H, m), 3.55 (2H, t, J=5.6Hz), 3.6-3.7 (2H, m), 3.73 (1H, d, J=16.1 Hz), 3.8-3.9 (1H, m), 3.97(2H, t, J=6.2 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 243-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1,1-di-(methyl)ethyl]ureido}propoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using 2-amino-2-methyl-1-propanol instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.5 (6H, m), 1.22 (6H, s), 1.85-1.95 (2H, m),2.8-2.95 (1H, m), 3.24 (2H, t, J=6.6 Hz), 3.25-3.45 (4H, m), 3.5 (2H,s), 3.6-3.7 (2H, m), 3.73 (1H, d, J=15.8 Hz), 3.8-3.9 (1H, m), 3.96 (2H,t, J=6.2 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 253-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{3-[2-(pyrrolidin-1-yl)ethyl]ureido}propoxy)phenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using 1-(2-aminoethyl)pyrrolidine instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.75-1.85 (4H, m), 1.85-1.95(2H, m), 2.5-2.65 (6H, m), 2.85-2.95 (1H, m), 3.2-3.45 (8H, m), 3.6-3.7(2H, m), 3.73 (1H, d, J=15.8 Hz), 3.8-3.9 (1H, m), 3.97 (2H, t, J=6.0Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 263-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1,1-bis-(hydroxymethyl)ethyl]ureido}propoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using tris(hydroxymethyl)-aminomethane instead of4-(2-aminoethyl)morpholine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-1.95 (2H, m), 2.8-2.95 (1H,m), 3.2-3.45 (6H, m), 3.55-3.7 (8H, m), 3.73 (1H, d, J=16.0 Hz), 3.8-3.9(1H, m), 3.97 (2H, t, J=6.1 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m),7.05-7.15 (2H, m)

Example 273-(β-D-Glucopyranosyloxy)-4-{[4-(3-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonylamino}propoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 1-(2-hydroxyethyl)piperazine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.4-2.55 (6H, m), 2.75-2.85 (1H, m), 3.25-3.45 (10H, m), 3.55-3.75 (5H,m), 3.75-3.85 (1H, m), 3.96 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.61(1H, dd, J=8.5 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6 Hz), 6.85 (1H, d, J=8.5Hz)

Example 283-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethyl]ureido}propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)-morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.19 (3H, s), 1.85-1.95 (2H,m), 2.29 (3H, s), 2.75-2.85 (1H, m), 3.2-3.4 (6H, m), 3.5-3.75 (7H, m),3.75-3.85 (1H, m), 3.96 (2H, t, J=6.2 Hz), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.6 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.6 Hz)

Example 293-(β-D-Glucopyranosyloxy)-4-{[4-(3-{3-[2-hydroxy-1,1-di-(methyl)ethyl]ureido}propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.23 (6H, s), 1.8-1.95 (2H, m),2.29 (3H, s), 2.75-2.85 (1H, m), 3.24 (2H, t, J=6.8 Hz), 3.25-3.4 (4H,m), 3.5 (2H, s), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.96 (2H, t,J=6.2 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.71 (1H,d, J=2.6 Hz), 6.85 (1H, d, J=8.5 Hz)

Example 303-(β-D-Glucopyranosyloxy)-4-[(4-{3-[3-(2-hydroxyethyl)-ureido]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-aminoethanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.29 (3H,s), 2.75-2.85 (1H, m), 3.22 (2H, t, J=5.7 Hz), 3.25-3.4 (6H, m), 3.55(2H, t, J=5.7 Hz), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 3.96 (2H, t,J=6.2 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.2 Hz, 2.4 Hz), 6.71 (1H,d, J=2.4 Hz), 6.85 (1H, d, J=8.2 Hz)

Example 314-{[4-(2-{3-[1-Carbamoyl-1-(methyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methylpropionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.44 (6H, s), 2.29 (3H, s),2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.44 (2H, t, J=5.3 Hz), 3.55-3.75(3H, m), 3.75-3.85 (1H, m), 3.95 (2H, t, J=5.3 Hz), 4.95-5.05 (1H, m),6.63 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.72 (1H, d, J=2.6 Hz), 6.86 (1H, d,J=8.5 Hz)

Example 323-(β-D-Glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.2 (3H, s), 2.29 (3H, s),2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.43 (2H, t, J=5.3 Hz), 3.5-3.75(7H, m), 3.75-3.85 (1H, m), 3.94 (2H, t, J=5.3 Hz), 4.95-5.05 (1H, m),6.63 (1H, dd, J=8.3 Hz, 2.7 Hz), 6.73 (1H, d, J=2.7 Hz), 6.86 (1H, d,J=8.3 Hz)

Example 333-(β-D-Glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1,1-di-(methyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 19 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 4-(2-aminoethyl)morpholine, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.23 (6H, s), 2.29 (3H, s),2.75-2.85 (1H, m), 3.25-3.4 (4H, m), 3.42 (2H, t, J=5.3 Hz), 3.52 (2H,s), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.94 (2H, t, J=5.3 Hz),4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.3 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5Hz), 6.86 (1H, d, J=8.3 Hz)

Example 343-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.29 g) in dichloromethane (5 mL) were added triethylamine (0.08 mL)and methanesulfonyl chloride (0.04 mL), and the mixture was stirred atroom temperature overnight. The reaction mixture was poured into 0.5mol/L hydrochloric acid, and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole.This material was dissolved in N,N-dimethylformamide (3 mL). To thesolution was added 1-(2-hydroxyethyl)piperazine (0.13 g), and themixture was stirred at 60° C. for 9 hours. The reaction mixture waspoured into water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water twice, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1-5/1) togive the title compound (91 mg).

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.81 (3H, s), 1.9-2.0 (5H, m),2.02 (3H, s), 2.07 (3H, s), 2.26 (3H, s), 2.3-2.75 (12H, m), 2.75-2.9(1H, m), 3.49 (1H, d, J=16.4 Hz), 3.55-3.7 (3H, m), 3.8-3.9 (1H, m),3.9-4.0 (2H, m), 4.1-4.2 (1H, m), 4.3 (1H, dd, J=12.3 Hz, 3.8 Hz),5.15-5.3 (3H, m), 5.55 (1H, d, J=8.3 Hz), 6.57 (1H, dd, J=8.6 Hz, 2.7Hz), 6.68 (1H, d, J=2.7 Hz), 6.79 (1H, d, J=8.6 Hz)

Example 353-(β-D-Glucopyranosyloxy)-4-[(4-{3-[4-(2-hydroxyethyl)-piperazin-1-yl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[4-(2-hydroxyethyl)-piperazin-1-yl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H, s),2.3-2.85 (13H, m), 3.25-3.4 (4H, m), 3.6-3.75 (5H, m), 3.75-3.85 (1H,m), 3.96 (2H, t, J=6.2 Hz), 4.95-5.1 (1H, m), 6.6 (1H, dd, J=8.5 Hz, 2.4Hz), 6.69 (1H, d, J=2.4 Hz), 6.84 (1H, d, J=8.5 Hz)

Reference Example 343-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N′-(cyano)-S-(methyl)isothioureido]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.19 g) in 2-propanol (2 mL) was added S,S′-dimethyl-N-cyanodithioiminocarbonate (57 mg), and the mixture wasstirred at room temperature for 4 hours. The reaction mixture waspurified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=1/1-dichloromethane/methanol=20/1) to give the title compound(0.19 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.91 (3H, s), 1.97 (3H, s),2.0-2.1 (8H, m), 2.56 (3H, s), 2.85-3.0 (1H, m), 3.5-3.65 (4H, m),3.9-4.05 (3H, m), 4.11 (1H, dd, J=12.4 Hz, 2.3 Hz), 4.29 (1H, dd, J=12.4Hz, 4.0 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48 (1H, d, J=8.0Hz), 6.75-6.85 (2H, m), 7.0-7.1 (2H, m)

Example 364-({4-[3-(2-Cyano-3-methylguanidino)propoxy]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

Methylamine (40% methanol solution, 2 mL) was added to3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N′-(cyano)-S-(methyl)isothioureido]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole(40 mg), and the mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in methanol (2 mL). To the solution was addedsodium methoxide (28% methanol solution, 0.02 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (18 mg).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.95-2.05 (2H, m) 2.76 (3H, s),2.85-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.7 (2H, m), 3.73 (1H, d,J=16.2 Hz), 3.8-3.9 (1H, m), 4.0 (2H, t, J=5.9 Hz), 5.05-5.1 (1H, m),6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 374-[(4-{3-[2-Cyano-3-(2-hydroxyethyl)guanidino]propoxy}-phenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-[(3-[N′-(cyano)-S-(methyl)isothioureido]propoxyphenyl)methyl]-5-isopropyl-1H-pyrazole(30 mg) in methanol (1 mL) was added 2-aminoethanol (0.5 mL), and themixture was stirred at 50° C. overnight. After cooling to roomtemperature, to the reaction mixture was added sodium methoxide (28%methanol solution, 0.02 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by solid phase extractionon ODS (washing solvent: distilled water, eluent: methanol) to give thetitle compound (15 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.95-2.05 (2H, m), 2.8-2.95 (1H,m), 3.25-3.45 (6H, m), 3.5-3.7 (6H, m), 3.73 (1H, d, J=15.8 Hz), 3.8-3.9(1H, m), 4.0 (2H, t, J=5.9 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m),7.05-7.15 (2H, m)

Example 383-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[3-(sulfamoylamino)propoxy]phenyl}methyl)-1H-pyrazole

To a solution of chlorosulfonyl isocyanate (0.022 mL) in acetonitrile (1mL) was added water (0.005 mL), and the mixture was stirred at roomtemperature for 10 minutes. This reaction mixture was added to asolution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole(51 mg) and triethylamine (0.052 mL) in dichloromethane (2 mL), and themixture was stirred at room temperature overnight. The reaction mixturewas poured into water, and the resulting mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: dichloromethane/methanol=30/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(sulfamoylamino)propoxy]phenyl}-methyl)-1H-pyrazole(18 mg). This material was dissolved in methanol (2 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.01 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (3 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.95-2.05 (2H, m), 2.8-2.95 (1H,m), 3.21 (2H, t, J=6.8 Hz), 3.25-3.45 (4H, m), 3.6-3.8 (3H, m), 3.84(1H, d, J=11.6 Hz), 4.02 (2H, t, J=6.0 Hz), 5.0-5.15 (1H, m), 6.75-6.85(2H, m), 7.05-7.15 (2H, m)

Example 393-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(carbamoylmethylamino)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(98 mg) in tetrahydrofuran (2 mL) were added2-(2-nitrobenzenesulfonylamino)acetoamide (40 mg), triphenylphosphine(45 mg) and diethyl azodicarboxylate (40% toluene solution, 0.1 mL), andthe mixture was stirred at room temperature overnight. The reactionmixture was purified by column chromatography on silica gel (eluent:ethyl acetate-dichloromethane/methanol=10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[N-(2-nitrobenzenesulfonyl)-N-(carbamoylmethyl)amino]propoxy}-2-methylphenyl)methyl]-1H-pyrazole(92 mg). This material was dissolved in acetonitrile (1 mL). To thesolution were added cesium carbonate (0.14 g) and thiophenol (0.012 mL),and the mixture was stirred at room temperature for 1 hour. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with brine, and driedover sodium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1-5/1) to give the title compound (57 mg).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.83 (3H, s), 1.9-2.05 (11H, m),2.26 (3H, s), 2.75-2.9 (3H, m), 3.28 (2H, s), 3.53 (1H, d, J=16.1 Hz),3.58 (1H, d, J=16.1 Hz), 3.85-3.95 (1H, m), 4.01 (2H, t, J=6.3 Hz), 4.06(1H, dd, J=12.4 Hz, 2.3 Hz), 4.27 (1H, dd, J=12.4 Hz, 4.2 Hz), 5.0-5.15(2H, m), 5.2-5.3 (1H, m), 5.43 (1H, d, J=8.0 Hz), 6.61 (1H, dd, J=8.5Hz, 2.6 Hz), 6.71 (1H, d, J=2.6 Hz), 6.77 (1H, d, J=8.5 Hz)

Example 403-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(carbamoylmethylamino)propoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.85-2.0 (8H, m), 2.01 (3H, s),2.02 (3H, s), 2.78 (2H, t, J=6.9 Hz), 2.85-3.0 (1H, m), 3.27 (2H, s),3.59 (2H, s), 3.9-4.0 (1H, m), 4.01 (2H, t, J=6.2 Hz), 4.11 (1H, dd,J=12.5 Hz, 2.3 Hz), 4.3 (1H, dd, J=12.5 Hz, 4.0 Hz), 5.05-5.15 (2H, m),5.25-5.35 (1H, m), 5.47 (1H, d, J=8.4 Hz), 6.75-6.85 (2H, m), 7.0-7.05(2H, m)

Example 413-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(carbamoyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand (S)-2-(2-nitrobenzenesulfonylamino)propionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-(2-nitrobenzenesulfonylamino)acetoamide, respectively.

H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.27 (3H, d, J=6.9 Hz), 1.85-2.0(8H, m), 2.01 (3H, s), 2.02 (3H, s), 2.65-2.8 (2H, m), 2.85-3.0 (1H, m),3.59 (2H, s), 3.9-4.05 (3H, m), 4.11 (1H, dd, J=12.5 Hz, 2.2 Hz), 4.3(1H, dd, J=12.5 Hz, 3.9 Hz), 5.05-5.15 (2H, m), 5.25-5.35 (1H, m), 5.48(1H, d, J=7.8 Hz), 6.75-6.85 (2H, m), 7.0-7.05 (2H, m)

Example 423-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-(1-carbamoyl-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-(2-nitrobenzenesulfonylamino)acetoamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.31 (6H, s), 1.85-2.0 (8H, m),2.01 (3H, s), 2.02 (3H, s), 2.6-2.8 (2H, m), 2.85-3.0 (1H, m), 3.59 (2H,s), 3.9-4.0 (1H, m), 4.02 (2H, t, J=6.1 Hz), 4.11 (1H, dd, J=12.5 Hz,2.6 Hz), 4.3 (1H, dd, J=12.5 Hz, 4.1 Hz), 5.05-5.15 (2H, m), 5.25-5.35(1H, m), 5.48 (1H, d, J=8.2 Hz), 6.75-6.85 (2H, m), 7.0-7.05 (2H, m)

Example 433-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(carbamoylmethylamino)ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.83 (3H, s), 1.96 (3H, s), 2.0(3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.75-2.9 (1H, m), 2.96 (2H, t,J=5.2 Hz), 3.32 (2H, s), 3.53 (1H, d, J=16.6 Hz), 3.59 (1H, d, J=16.6Hz), 3.85-3.95 (1H, m), 4.03 (2H, t, J=5.2 Hz), 4.06 (1H, dd, J=12.3 Hz,2.0 Hz), 4.27 (1H, dd, J=12.3 Hz, 4.2 Hz), 5.0-5.15 (2H, m), 5.2-5.35(1H, m), 5.43 (1H, d, J=8.0 Hz), 6.64 (1H, dd, J=8.5 Hz, 2.3 Hz), 6.74(1H, d, J=2.3 Hz), 6.78 (1H, d, J=8.5 Hz)

Example 443-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-(carbamoyl)ethylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 39 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 3-(2-nitrobenzenesulfonylamino)propionamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-(2-nitrobenzenesulfonylamino)acetoamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.83 (3H, s), 1.96 (3H, s), 2.0(3H, s), 2.02 (3H, s), 2.26 (3H, s), 2.47 (2H, t, J=6.7 Hz), 2.75-2.9(1H, m), 2.9-3.05 (4H, m), 3.53 (1H, d, J=16.4 Hz), 3.59 (1H, d, J=16.4Hz), 3.85-3.95 (1H, m), 4.0-4.1 (3H, m), 4.27 (1H, dd, J=12.5 Hz, 4.1Hz), 5.0-5.15 (2H, m), 5.25-5.35 (1H, m), 5.43 (1H, d, J=8.2 Hz), 6.64(1H, dd, J=8.3 Hz, 2.6 Hz), 6.75 (1H, d, J=2.6 Hz), 6.79 (1H, d, J=8.3Hz)

Example 454-({4-[3-(Carbamoylmethylamino)propoxy]-2-methylphenyl}-methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(carbamoylmethylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H, s),2.7-2.85 (3H, m), 3.24 (2H, s), 3.25-3.4 (4H, m), 3.6-3.75 (3H, m),3.75-3.85 (1H, m), 4.01 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 464-({4-[3-(Carbamoylmethylamino)propoxy]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(carbamoylmethylamino)-propoxy]phenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-2.0 (2H, m), 2.75 (2H, t,J=6.9 Hz), 2.8-2.95 (1H, m), 3.25 (2H, s), 3.3-3.45 (4H, m), 3.6-3.7(2H, m), 3.73 (1H, d, J=16.3 Hz), 3.8-3.9 (1H, m), 4.02 (2H, t, J=6.0Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 474-[(4-{3-[(S)-1-(Carbamoyl)ethylamino]propoxy}phenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[(S)-1-(carbamoyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.26 (3H, d, J=7.0 Hz), 1.85-2.0(2H, m), 2.6-2.75 (2H, m), 2.8-2.95 (1H, m), 3.19 (1H, q, J=7.0 Hz),3.25-3.45 (4H, m), 3.6-3.7 (2H, m), 3.73 (1H, d, J=16.0 Hz), 3.8-3.9(1H, m), 4.0 (2H, t, J=6.2 Hz), 5.0-5.15 (1H, m), 6.75-6.85 (2H, m),7.05-7.15 (2H, m)

Example 484-[(4-{3-[1-Carbamoyl-1-(methyl)ethylamino]propoxy}phenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carbamoyl-1-(methyl)-ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.29 (6H, s), 1.85-1.95 (2H, m),2.65 (2H, t, J=7.1 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.7(2H, m), 3.73 (1H, d, J=15.9 Hz), 3.8-3.9 (1H, m), 4.02 (2H, t, J=5.9Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 494-({4-[2-(Carbamoylmethylamino)ethoxy]-2-methylphenyl}-methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(carbamoylmethylamino)-ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.75-2.85 (1H,m), 2.94 (2H, t, J=5.2 Hz), 3.25-3.4 (6H, m), 3.6-3.75 (3H, m),3.75-3.85 (1H, m), 4.02 (2H, t, J=5.2 Hz), 4.95-5.1 (1H, m), 6.64 (1H,dd, J=8.4 Hz, 2.5 Hz), 6.74 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)

Example 504-[(4-(2-[2-(Carbamoyl)ethylamino]ethoxy)-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-(carbamoyl)ethylamino]-ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.44 (2H, t,J=6.8 Hz), 2.7-2.85 (1H, m), 2.9 (2H, t, J=6.8 Hz), 2.95 (2H, t, J=5.1Hz), 3.25-3.4 (4H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.03 (2H, t,J=5.1 Hz), 4.95-5.05 (1H, m), 6.64 (1H, dd, J=8.5 Hz, 2.4 Hz), 6.74 (1H,d, J=2.4 Hz), 6.86 (1H, d, J=8.5 Hz)

Example 514-[(4-{3-[1-Carbamoyl-1-(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-(β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.25 g) in tetrahydrofuran (2 mL) were added2-methyl-2-(2-nitrobenzenesulfonylamino)-propionamide (0.14 g),triphenylphosphine (0.12 g) and diethyl azodicarboxylate (40% toluenesolution, 0.26 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was purified by column chromatography onsilica gel (eluent: n-hexane/ethylacetate=1/4-dichloromethane/methanol=20/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{N-(2-nitrobenzenesulfonyl)-N-[1-carbamoyl-1-(methyl)ethyl]amino}propoxy)-2-methylphenyl]-methyl}-1H-pyrazole(0.32 g). This material was dissolved in acetonitrile (3 mL). To thesolution were added cesium carbonate (0.46 g) and thiophenol (0.038 mL),and the mixture was stirred at room temperature for 1 hour. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with water and brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethylacetate=1/5-dichloromethane/methanol=15/1-10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carbamoyl-1-(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(20 mg).

This material was dissolved in methanol (1 mL). To the solution wasadded sodium methoxide (28% methanol solution, 0.01 mL), and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (11 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.29 (6H, s), 1.85-1.95 (2H,m), 2.29 (3H, s), 2.65 (2H, t, J=6.9 Hz), 2.75-2.85 (1H, m), 3.25-3.4(4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 4.01 (2H, t, J=6.1 Hz),4.95-5.05 (1H, m), 6.61 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6Hz), 6.85 (1H, d, J=8.5 Hz)

Example 524-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 using 3-(2-nitrobenzenesulfonylamino)propionamide instead of2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.42 (2H, t, J=6.9 Hz), 2.7-2.9 (5H, m), 3.25-3.4 (4H, m), 3.6-3.75 (3H,m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.2 Hz), 4.95-5.05 (1H, m), 6.62(1H, dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.4Hz)

Example 533-(β-D-Glucopyranosyloxy)-4-[(4-{(R)-2-hydroxy-3-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethylamino]propoxy}-phenyl)methyl]-5-isopropyl-1H-pyrazole

A mixture of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole(0.55 g), (R)-1-(3-nitrobenzenesulfonyloxy)-2,3-epoxypropane (0.38 g)and cesium carbonate (0.57 g) in N,N-dimethylformamide (5 mL) wasstirred at room temperature for 24 hours. The reaction mixture waspoured into water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and brine successively,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) togive3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(R)-2,3-epoxypropoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole(0.4 g). This material (43 mg) was dissolved in ethanol (1.5 mL). To thesolution was added 2-amino-2-methyl-1,3-propanediol (51 mg), and themixture was stirred at 75° C. for 14 hours. To the reaction mixture wasadded 1 mol/L aqueous sodium hydroxide solution (0.28 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas directly purified by preparative reverse phase column chromatography(Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30mL/minute linear gradient, water/methanol 90/10-10/90) to give the titlecompound (12 mg).

H-NMR (CD₃OD) δ ppm: 1.0 (3H, s), 1.05-1.15 (6H, m), 2.68 (1H, dd,J=11.6 Hz, 8.1 Hz), 2.78 (1H, dd, J=11.6 Hz, 3.8 Hz), 2.8-2.95 (1H, m),3.25-3.55 (8H, m), 3.6-3.7 (2H, m), 3.73 (1H, d, J=16.1 Hz), 3.8-4.0(4H, m), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Examle 543-(β-D-Glucopyranosyloxy)-4-{[4-[(R)-2-hydroxy-3-(2-hydroxyethylamino)propoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 53 using 2-aminoethanol instead of2-amino-2-methyl-1,3-propanediol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 2.65-2.95 (5H, m), 3.25-3.45(4H, m), 3.6-3.8 (5H, m), 3.8-3.9 (1H, m), 3.91 (2H, d, J=5.4 Hz),4.0-4.1 (1H, m), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m)

Example 553-(β-D-Glucopyranosyloxy)-4-{[4-(3-guanidinopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(70 mg) in tetrahydrofuran (3 mL) was addedN-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.27 g), and themixture was stirred at 60° C. for 20 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole(50 mg). This material was dissolved in methanol (1 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.01 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(35 mg). This material was dissolved in methanol (2 mL). To the solutionwas added 10% palladium-carbon powder (15 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 2 hours. Theinsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(27 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.95-2.05 (2H, m), 2.29 (3H, s),2.75-2.9 (1H, m), 3.25-3.45 (6H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H,m), 4.01 (2H, t, J=5.7 Hz), 4.95-5.05 (1H, m), 6.64 (1H, dd, J=8.6 Hz,2.5 Hz), 6.73 (1H, d, J=2.5 Hz), 6.87 (1H, d, J=8.6 Hz)

Example 563-(β-D-Glucopyranosyloxy)-4-{[4-(2-guanidinoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 55 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.3 (3H, s), 2.75-2.9 (1H, m),3.25-3.4 (4H, m), 3.55 (2H, t, J=5.0 Hz), 3.6-3.75 (3H, m), 3.75-3.85(1H, m), 4.06 (2H, t, J=5.0 Hz), 5.02 (1H, d, J=7.0 Hz), 6.65 (1H, dd,J=8.5 Hz, 2.6 Hz), 6.75 (1H, d, J=2.6 Hz), 6.88 (1H, d, J=8.5 Hz)

Example 573-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-di-(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(1 g) in dichloromethane (16 mL) were added triethylamine (0.29 mL) andmethanesulfonyl chloride (0.15 mL), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(1.12 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(0.2 g) was dissolved in a mixed solvent of acetonitrile (2 mL) andethanol (2 mL). To the solution were added 2-amino-2-methyl-1-propanol(0.25 g) and a catalytic amount of sodium iodide, and the mixture wasstirred at 60° C. for 2 days. The reaction mixture was concentratedunder reduced pressure, and the residue was dissolved in methanol (3mL). To the solution was added sodium methoxide (28% methanol solution,0.16 mL), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent: methanol) to give the title compound (0.13 g).

¹H-NMR (CD₃OD) δ ppm: 1.0-1.15 (12H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.65-2.85 (3H, m), 3.25-3.4 (6H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H,m), 4.0 (2H, t, J=5.6 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.5 Hz,2.6 Hz), 6.71 (1H, d, J=2.6 Hz), 6.85 (1H, d, J=8.5 Hz)

Example 583-(β-D-Glucopyranosyloxy)-4-({4-[3-(2-hydroxyethylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using 2-aminoethanol instead of 2-amino-2-methyl-1-propanol.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.7-2.85 (5H, m), 3.25-3.4 (4H, m), 3.55-3.75 (5H, m), 3.75-3.85 (1H,m), 4.0 (2H, t, J=5.9 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.5 Hz,2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.5 Hz)

Example 593-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-(hydroxymethyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using 2-amino-1,3-propanediol instead of2-amino-2-methyl-1-propanol.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.65-2.9 (4H, m), 3.25-3.4 (4H, m), 3.54 (2H, dd, J=11.1 Hz, 5.8 Hz),3.55-3.75 (5H, m), 3.75-3.85 (1H, m), 4.01 (2H, t, J=6.0 Hz), 4.95-5.05(1H, m), 6.62 (1H, dd, J=8.6 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.85(1H, d, J=8.6 Hz)

Example 603-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-(hydroxymethyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.9-2.0 (2H, m), 2.65-2.75 (1H,m), 2.8-2.95 (3H, m), 3.25-3.45 (4H, m), 3.54 (2H, dd, J=11.2 Hz, 5.9Hz), 3.55-3.7 (4H, m), 3.73 (1H, d, J=15.8 Hz), 3.8-3.9 (1H, m), 4.02(2H, t, J=6.1 Hz), 5.0-5.15 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H,m)

Example 613-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-di-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.0-1.15 (12H, m), 1.85-2.0 (2H, m), 2.65-2.8 (2H,m), 2.8-2.95 (1H, m), 3.25-3.45 (6H, m), 3.6-3.8 (3H, m), 3.8-3.9 (1H,m), 3.95-4.05 (2H, m), 5.0-5.15 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15(2H, m)

Example 623-(β-D-Glucopyranosyloxy)-4-[(4-(2-[2-hydroxy-1-(hydroxymethyl)ethylamino]ethoxy)-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.7-2.85 (2H, m),3.04 (2H, t, J=5.2 Hz), 3.25-3.4 (4H, m), 3.55 (2H, dd, J=11.2 Hz, 5.8Hz), 3.6-3.75 (5H, m), 3.75-3.85 (1H, m), 4.06 (2H, t, J=5.2 Hz),4.95-5.1 (1H, m), 6.65 (1H, dd, J=8.5 Hz, 2.7 Hz), 6.75 (1H, d, J=2.7Hz), 6.87 (1H, d, J=8.5 Hz)

Example 633-(β-D-Glucopyranosyloxy)-4-({4-[2-(2-hydroxyethylamino)-ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-aminoethanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.75-2.85 (3H,m), 2.99 (2H, t, J=5.2 Hz), 3.25-3.4 (4H, m), 3.6-3.75 (5H, m),3.75-3.85 (1H, m), 4.05 (2H, t, J=5.2 Hz), 4.95-5.1 (1H, m), 6.65 (1H,dd, J=8.4 Hz, 2.4 Hz), 6.74 (1H, d, J=2.4 Hz), 6.87 (1H, d, J=8.4 Hz)

Example 643-(β-D-Glucopyranosyloxy)-5-isopropyl-4-({4-[3-(3-pyridylmethylamino)propoxy]phenyl}methyl)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazoleand 3-picolylamine instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.77 (2H, t,J=7.2 Hz), 2.8-2.95 (1H, m), 3.25-3.45 (4H, m), 3.6-3.7 (2H, m), 3.73(1H, d, J=16.3 Hz), 3.75-3.9 (3H, m), 4.0 (2H, t, J=6.0 Hz), 5.0-5.1(1H, m), 6.7-6.8 (2H, m), 7.05-7.15 (2H, m), 7.35-7.45 (1H, m), 7.8-7.85(1H, m), 8.4-8.45 (1H, m), 8.5-8.55 (1H, m)

Example 654-{[4-(2-Aminoethoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 6 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.7-2.85 (1H, m),2.99 (2H, t, J=5.2 Hz), 3.25-3.4 (4H, m), 3.55-3.75 (3H, m), 3.75-3.85(1H, m), 3.97 (2H, t, J=5.2 Hz), 4.95-5.05 (1H, m), 6.64 (1H, dd, J=8.6Hz, 2.7 Hz), 6.74 (1H, d, J=2.7 Hz), 6.86 (1H, d, J=8.6 Hz)

Example 663-(β-D-Glucopyranosyloxy)-4-({4-[3-(3-hydroxypropylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using 3-amino-1-propanol instead of2-amino-2-methyl-1-propanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.7-1.8 (2H, m), 1.9-2.0 (2H,m), 2.29 (3H, s), 2.65-2.85 (5H, m), 3.25-3.4 (4H, m), 3.55-3.75 (5H,m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.61(1H, dd, J=8.5 Hz, 2.5 Hz), 6.7 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.5Hz)

Example 673-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using 2-amino-2-methyl-1,3-propanediol instead of2-amino-2-methyl-1-propanol.

¹H-NMR (CD₃OD) δ ppm: 1.01 (3H, s), 1.05-1.15 (6H, m), 1.85-2.0 (2H, m),2.29 (3H, s), 2.7-2.85 (3H, m), 3.25-3.4 (4H, m), 3.4-3.55 (4H, m),3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.01 (2H, t, J=6.0 Hz), 4.95-5.05(1H, m), 6.62 (1H, dd, J=8.3 Hz, 2.6 Hz), 6.72 (1H, d, J=2.6 Hz), 6.84(1H, d, J=8.3 Hz)

Example 683-(β-D-Glucopyranosyloxy)-4-[(4-{2-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethylamino]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1,3-propanediol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.01 (3H, s), 1.05-1.15 (6H, m), 2.29 (3H, s),2.7-2.85 (1H, m), 2.92 (2H, t, J=5.3 Hz), 3.25-3.4 (4H, m), 3.4-3.55(4H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.02 (2H, t, J=5.3 Hz),4.95-5.05 (1H, m), 6.64 (1H, dd, J=8.4 Hz, 2.7 Hz), 6.74 (1H, d, J=2.7Hz), 6.86 (1H, d, J=8.4 Hz)

Example 693-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand tris(hydroxymethyl)-aminomethane instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.85-2.0 (2H, m), 2.75-2.95 (3H,m), 3.25-3.4 (4H, m), 3.56 (6H, s), 3.6-3.75 (3H, m), 3.8-3.9 (1H, m),4.02 (2H, t, J=6.1 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15(2H, m)

Example 703-(β-D-Glucopyranosyloxy)-4-({4-[2-(3-hydroxypropylamino)-ethoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 3-amino-1-propanol instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-amino-2-methyl-1-propanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.7-1.8 (2H, m), 2.29 (3H, s),2.65-2.85 (3H, m), 2.94 (2H, t, J=5.2 Hz), 3.25-3.4 (4H, m), 3.55-3.75(5H, m), 3.75-3.85 (1H, m), 4.03 (2H, t, J=5.2 Hz), 4.95-5.05 (1H, m),6.64 (1H, dd, J=8.1 Hz, 2.4 Hz), 6.74 (1H, d, J=2.4 Hz), 6.86 (1H, d,J=8.1 Hz)

Example 713-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 57 using tris(hydroxymethyl)-aminomethane instead of2-amino-2-methyl-1-propanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.28 (3H,s), 2.75-2.85 (3H, m), 3.25-3.4 (4H, m), 3.56 (6H, s), 3.6-3.75 (3H, m),3.75-3.85 (1H, m), 4.01 (2H, t, J=6.0 Hz), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.5 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.84 (1H, d, J=8.5 Hz)

Reference Example 35 2-[2-Amino-2-(methyl)propionylamino]ethanol

To a solution of 2-benzyloxycarbonylamino-2-(methyl)-propionic acid (1g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole(889 mg), and the mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added 2-aminoethanol (0.38 mL), and the mixturewas stirred at room temperature for 2 hours. The reaction mixture waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1) to give2-[2-benzyloxycarbonylamino-2-(methyl)propionylamino]ethanol (973 mg).

This material was dissolved in methanol (5 mL). To the solution wasadded 10% palladium-carbon powder (200 mg), and the mixture was stirredat room temperature under a hydrogen atmosphere overnight. The insolublematerial was removed by filtration, and thesolventofthefiltratewasremovedunderreducedpressure to give the title compound(505 mg).

¹H-NMR (CD₃OD) δ ppm: 1.31 (6H, s), 3.25-3.35 (2H, m), 3.6 (2H, t, J=5.7Hz)

Reference Example 36 4-Methyl-1-[2-amino-2-(methyl)propionyl]piperazine

The title compound was prepared in a similar manner to that described inReference Example 35 using 1-methylpiperazine instead of 2-aminoethanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.24 (6H, s), 1.83 (2H, brs), 2.16 (3H, s), 2.26(4H, t, J=5.0 Hz), 3.5-3.95 (4H, br)

Reference Example 372-[2-Amino-2-(methyl)propionylamino]-2-methyl-1-propanol

The title compound was prepared in a similar manner to that described inReference Example 35 using 2-amino-2-methyl-1-propanol instead of2-aminoethanol.

¹H-NMR (CD₃OD) δ ppm: 1.28 (12H, s), 3.55 (2H, s)

Reference Example 38 3-[2-Amino-2-(methyl)propionylamino]-1-propanol

The title compound was prepared in a similar manner to that described inReference Example 35 using 3-amino-1-propanol instead of 2-aminoethanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.16 (6H, s), 1.5-1.6 (2H, m), 1.89 (2H, brs),3.05-3.15 (2H, m), 3.35-3.45 (2H, m), 4.43 (1H, t, J=5.3 Hz), 7.8-7.95(1H, br)

Reference Example 39 N-[2-Amino-2-(methyl)propionyl]morpholine

The title compound was prepared in a similar manner to that described inReference Example 35 using morpholine instead of 2-aminoethanol.

H-NMR (DMSO-d₆) δ ppm: 1.25 (6H, s), 1.75-2.3 (2H, br), 3.45-3.6 (4H,m), 3.65-3.95 (4H, br)

Example 723-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.77 g) in dichloromethane (5 mL) were added triethylamine (0.26 mL)and methanesulfonyl chloride (0.12 mL), and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was poured into0.5 mol/L hydrochloric acid, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with water and brine,and dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)-propoxy]phenyl}methyl)-1H-pyrazole(0.85 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl}-methyl)-1H-pyrazole(0.2 g) was dissolved in a mixed solvent of acetonitrile (1.5 mL) andethanol (1.5 mL). To the solution were added2-[2-amino-2-(methyl)propionylamino]ethanol (0.25 g) and a catalyticamount of sodium iodide, and the mixture was stirred at 60° C. for 4days. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1-10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole(0.13 g). This material was dissolved in methanol (3 mL). To thesolution was added sodium methoxide (28% methanol solution, 0.05 mL),and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent: methanol) to give the title compound (93 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.28 (6H, s), 1.8-1.95 (2H, m),2.63 (2H, t, J=6.9 Hz), 2.85-2.95 (1H, m), 3.2-3.4 (6H, m), 3.55 (2H, t,J=5.8 Hz), 3.6-3.9 (4H, m), 4.03 (2H, t, J=6.2 Hz), 5.0-5.1 (1H, m),6.7-6.85 (2H, m), 7.0-7.15 (2H, m)

Example 733-(β-D-Glucopyranosyloxy)-4-{[4-(3-(1-[(4-methylpiperazin-1-yl)carbonyl]-1-(methyl)ethylamino}propoxy)phenyl]methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using 4-methyl-1-[2-amino-2-(methyl)propionyl]piperazineinstead of 2-[2-amino-2-(methyl)propionylamino]ethanol.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.34 (6H, s), 1.8-1.95 (2H, m),2.19 (3H, s), 2.3-2.4 (4H, m), 2.66 (2H, t, J=6.3 Hz), 2.8-2.95 (1H, m),3.3-3.4 (4H, m), 3.55-4.15 (10H, m), 5.0-5.15 (1H, m), 6.7-6.8 (2H, m),7.05-7.15 (2H, m)

Example 743-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[2-hydroxy-1,1-di-(methyl)ethylcarbamoyl]-1-(methyl)ethylamino}propoxy)-phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using2-[2-amino-2-(methyl)-propionylamino]-2-methyl-1-propanol instead of2-[2-amino-2-(methyl)propionylamino]ethanol.

H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.24 (6H, s), 1.25 (6H, s),1.85-1.95 (2H, m), 2.64 (2H, t, J=6.9 Hz), 2.8-2.95 (1H, m), 3.3-3.45(4H, m), 3.48 (2H, s), 3.6-3.9 (4H, m), 4.03 (2H, t, J=6.1 Hz), 5.05-5.1(1H, m), 6.75-6.8 (2H, m), 7.05-7.15 (2H, m)

Example 753-(β-D-Glucopyranosyloxy)-4-[(4-{3-[1-(3-hydroxypropylcarbamoyl)-1-(methyl)ethylamino]propoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using 3-[2-amino-2-(methyl)-propionylamino]-1-propanolinstead of 2-[2-amino-2-(methyl)propionylamino]ethanol.

H-NMR (CD₃OD) δ ppm: 1.1-1.15 (6H, m), 1.27 (6H, s), 1.55-1.7 (2H, m),1.85-1.95 (2H, m), 2.62 (2H, t, J=6.8 Hz), 2.8-2.95 (1H, m), 3.23 (2H,t, J=6.7 Hz), 3.3-3.4 (4H, m), 3.53 (2H, t, J=6.2 Hz), 3.6-3.85 (4H, m),4.03 (2H, t, J=6.0 Hz), 5.0-5.1 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15(2H, m)

Example 763-(β-D-Glucopyranosyloxy)-4-{[4-(3-{1-[(morpholin-4-yl)-carbonyl]-1-(methyl)ethylamino}propoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using N-(2-amino-2-(methyl)-propionyl]morpholine instead of2-[2-amino-2-(methyl)-propionylamino]ethanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.35 (6H, s), 1.8-1.95 (2H, m),2.6-2.75 (2H, m), 2.8-2.95 (1H, m), 3.3-3.4 (4H, m), 3.45-4.15 (14H, m),5.0-5.15 (1H, m), 6.7-6.8 (2H, m), 7.05-7.15 (2H, m)

Example 773-(β-D-Glucopyranosyloxy)-4-[(4-{2-[3-(2-hydroxyethyl)-2-methanesulfonylguanidino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of dichlorophenoxymethane (1 g) in acetonitrile (10 mL)was added methanesulfonamide (0.39 g) under ice-cooling, and the mixturewas stirred at room temperature for 48 hours. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andthe resuling mixture was extracted with ethyl acetate. The organic layerwas washed with water and brine, and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure to give1-(N-methanesulfonylimino)-1,1-diphenoxymethane (0.95 g). To a solutionof3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(50 mg) in tetrahydrofuran (1 mL) was added1-(N-methanesulfonylimino)-1,1-diphenoxymethane (26 mg) underice-cooling, and the mixture was stirred at room temperature for 1 hour.To the reaction mixture was added 2-aminoethanol (49 mg), and themixture was stirred at 60 C.° overnight. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inmethanol (2 mL). To the solution was added sodium methoxide (28%methanol solution, 0.008 mL), and the mixture was stirred at roomtemperature for 3 hours. To the reaction mixture was added acetic acid(0.01 mL). The resulting mixture was concentrated under reducedpressure, and the residue was purified by solid phase extraction on ODS(washing solvent: distilled water, eluent:

-   -   methanol) to give the title compound (38 mg).

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.28 (3H, s), 2.75-2.85 (1H, m),2.9 (3H, s), 3.25-3.4 (6H, m), 3.6 (2H, t, J=5.3 Hz), 3.6-3.75 (5H, m),3.8 (1H, d, J=12.0 Hz), 4.05 (2H, t, J=5.3 Hz), 4.95-5.05 (1H, m), 6.65(1H, dd, J=8.1 Hz, 2.4 Hz), 6.76 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.1Hz)

Example 784-[(4-{3-[(S)-5-Benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand (S)-2-amino-6-(benzyloxycarbonylamino)hexanamide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-[2-amino-2-(methyl)propionylamino]ethanol, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.3-1.45 (2H, m), 1.45-1.7 (4H,m), 1.85-2.0 (2H, m), 2.28 (3H, s), 2.6-2.85 (3H, m), 3.05-3.15 (3H, m),3.25-3.4 (4H, m), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0Hz), 4.95-5.1 (3H, m), 6.61 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.7 (1H, d,J=2.5 Hz), 6.84 (1H, d, J=8.4 Hz), 7.2-7.4 (5H, m)

Example 794-[(4-{3-[(S)-5-Amino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(0.17 g) in methanol (4 mL) was added 10% palladium-carbon powder (30mg), and the mixture was stirred at room temperature under a hydrogenatmosphere for 1 hour. The insoluble material was removed by filtration,and the filtrate was concentrated under reduced pressure to give thetitle compound (0.13 g).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.3-1.7 (6H, m), 1.85-2.0 (2H,m), 2.29 (3H, s), 2.6-2.9 (5H, m), 3.08 (1H, t, J=6.6 Hz), 3.25-3.4 (4H,m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.0 (2H, t, J=6.1 Hz), 5.01(1H, d, J=7.0 Hz), 6.61 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.7 (1H, d, J=2.6Hz), 6.84 (1H, d, J=8.4 Hz)

Example 804-[(4-{3-[(S)-2,5-Diaminopentanoylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand (S)-2,5-bis-(benzyloxycarbonylamino)pentanoic acid instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-benzyloxycarbonylaminoacetic acid, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.35-1.75 (4H, m), 1.9-2.0 (2H,m), 2.29 (3H, s), 2.59 (2H, t, J=6.9 Hz), 2.75-2.9 (1H, m), 3.2-3.5 (7H,m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.97 (2H, t, J=6.0 Hz), 5.01(1H, d, J=7.3 Hz), 6.62 (1H, dd, J=8.5 Hz, 2.3 Hz), 6.72 (1H, d, J=2.3Hz), 6.85 (1H, d, J=8.5 Hz)

Reference Example 401-Benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]-piperazine

To a solution of diethyl dimethylmalonate (3 g) in ethanol (5 mL) wasadded a solution of sodium hydroxide (0.64 g) in water (2 mL), and themixture was stirred at room temperature for 5 days. The reaction mixturewas concentrated under reduced pressure, and the residue was acidifiedby addition of 2 mol/L hydrochloric acid. The resulting mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure to give mono-ethyl dimethylmalonate (2.43 g).

To a solution of the obtained mono-ethyl dimethylmalonate (1 g) inN,N-dimethylformamide (20 mL) were added 1-(benzyloxycarbonyl)piperazine(1.38 g), 1-hydroxybenzotriazole (0.93 g), triethylamine (1.31 mL) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.4 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was poured into water, and the resulting mixture was extractedwith diethyl ether. The extract was washed with a saturated aqueoussodium hydrogen carbonate solution, water and brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give1-benzyloxycarbonyl-4-[2-ethoxycarbonyl-2-(methyl)propionyl]piperazine(1.77 g). This material was dissolved in ethanol (5 mL). To the solutionwas added 2 mol/L aqueous sodium hydroxide solution (2.93 mL), and themixture was stirred at 55° C. overnight. The reaction mixture was pouredinto water, and the resulting mixture was washed with diethyl ether. Theaqueous layer was acidified by addition of 2 mol/L hydrochloric acid,and the mixture was extracted with diethyl ether. The extract was washedwith brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give the title compound (0.28 g).

H-NMR (CDCl₃) δ ppm: 1.48 (6H, s), 3.25-3.7 (8H, m), 5.14 (2H, s),7.3-7.4 (5H, m)

Example 813-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(2-{2-methyl-2-[(piperazin-1-yl)carbonyl]propionylamino}ethoxy)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 13 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]piperazineinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-benzyloxycarbonylaminoacetic acid, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.37 (6H, s), 2.3 (3H, s),2.35-2.9 (5H, m), 3.1-3.75 (13H, m), 3.81 (1H, d, J=11.5 Hz), 4.02 (2H,t, J=5.4 Hz), 5.02 (1H, d, J=7.4 Hz), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz),6.72 (1H, d, J=2.5 Hz), 6.86 (1H, d, J=8.4 Hz)

Reference Example 41N,N-Dimethyl-N′-(2-nitrobenzenesulfonyl)-1,3-diaminopropane

To a solution of N,N-dimethyl-1,3-diaminopropane (0.92 g) andtriethylamine (0.95 mL) in dichloromethane (10 mL) was added2-nitrobenzenesulfonyl chloride (1 g), and the mixture was stirred atroom temperature overnight. The reaction mixture was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1) togive the title compound (1.26 g).

¹H-NMR (CDCl₃) δ ppm: 1.7-1.8 (2H, m), 2.28 (6H, s), 2.46 (2H, t, J=5.9Hz), 3.15-3.25 (2H, m), 7.65-7.75 (2H, m), 7.8-7.85 (1H, m), 8.05-8.15(1H, m)

Reference Example 42 Methyl 3-(2-nitrobenzenesulfonylamino)propionate

The title compound was prepared in a similar manner to that described inReference Example 2 using methyl 3-aminopropionate hydrochloride insteadof glycinamide hydrochloride.

H-NMR (CDCl₃) δ ppm: 2.61 (2H, t, J=6.2 Hz), 3.37 (2H, q, J=6.2 Hz),3.69 (3H, s), 5.96 (1H, t, J=6.2 Hz), 7.7-7.8 (2H, m), 7.85-7.9 (1H, m),8.1-8.2 (1H, m)

Reference Example 434-Methyl-1-[3-(2-nitrobenzenesulfonylamino)propionyl]-piperazine

To a solution of methyl 3-(2-nitrobenzenesulfonylamino)-propionate (6.15g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodiumhydroxide solution (20 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was acidified by addition of2 mol/L hydrochloric acid (55 mL), and the resulting mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was treated with n-hexane andethyl acetate. The precipitated crystals were collected by filtration,washed with n-hexane and dried under reduced pressure to give3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution ofthe obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) intetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g),and the mixture was stirred at room temperature for 2 hours. To thereaction mixture was added 1-methylpiperazine (0.46 g), and the mixturewas stirred at 50° C. for 3 days. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on aminopropylated silica gel (eluent:dichloromethane/methanol=40/1) to give the title compound (0.61 g).

¹H-NMR (CDCl₃) δ ppm: 2.25-2.4 (7H, m), 2.61 (2H, t, J=5.7 Hz), 3.3-3.45(4H, m), 3.55-3.65 (2H, m), 7.65-7.75 (2H, m), 7.8-7.9 (1H, m), 8.1-8.15(1H, m)

Reference Example 444-Benzyl-1-[3-(2-nitrobenzenesulfonylamino)propionyl]-piperazine

The title compound was prepared in a similar manner to that described inReference Example 43 using 1-benzylpiperazine instead of1-methylpiperazine.

¹H-NMR (CDCl₃) δ ppm: 2.35-2.45 (4H, m), 2.59 (2H, t, J=5.8 Hz),3.3-3.45 (4H, m), 3.52 (2H, s), 3.55-3.65 (2H, m), 7.2-7.35 (5H, m),7.65-7.75 (2H, m), 7.8-7.9 (1H, m), 8.05-8.15 (1H, m)

Reference Example 454-(2-Hydroxyethyl)-1-[3-(2-nitrobenzenesulfonylamino)-propionyl]piperazine

The title compound was prepared in a similar manner to that described inReference Example 43 using 1-(2-hydroxyethyl)-piperazine instead of1-methylpiperazine.

H-NMR (CDCl₃) δ ppm: 2.4-2.65 (8H, m), 3.37 (2H, t, J=5.8 Hz), 3.43 (2H,t, J=5.0 Hz), 3.55-3.7 (4H, m), 7.7-7.75 (2H, m), 7.8-7.9 (1H, m),8.1-8.15 (1H, m)

Reference Example 464-(2-Acetoxyethyl)-1-[3-(2-nitrobenzenesulfonylamino)-propionyl]piperazine

To a solution of4-(2-hydroxyethyl)-1-[3-(2-nitrobenzenesufonylamino)propionyl]piperazine(1.15 g) and pyridine (1.47 mL) in dichloromethane (10 mL) was addedacetic anhydride (1.72 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=1/2-dichloromethane/methanol=10/1) to give the title compound(0.38 g).

H-NMR (CDCl₃) δ ppm: 2.07 (3H, s), 2.4-2.55 (4H, m), 2.55-2.7 (4H, m),3.3-3.45 (4H, m), 3.55-3.65 (2H, m), 4.05-4.15 (2H, m), 6.34 (1H, t,J=6.5 Hz), 7.7-7.75 (2H, m), 7.8-7.9 (1H, m), 8.1-8.15 (1H, m)

Example 823-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[3-(di-methylamino)propylamino]propoxy}-2-methylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 usingN,N-dimethyl-N′-(2-nitrobenzenesulfonyl)-1,3-diaminopropane instead of2-methyl-(2-nitrobenzenesulfonylamino)propionamide.

¹H-NMR (CD₃OD) δ ppm: 0.05-1.15 (6H, m), 1.6-1.75 (2H, m), 1.85-2.0 (2H,m), 2.22 (6H, s), 2.29 (3H, s), 2.3-2.4 (2H, m), 2.61 (2H, t, J=7.4 Hz),2.7-2.85 (3H, m), 3.25-3.4 (4H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m),3.99 (2H, t, J=6.0 Hz), 4.95-5.1 (1H, m), 6.61 (1H, dd, J=8.2 Hz, 2.5Hz), 6.7 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.2 Hz)

Example 833-(β-D-Glucopyranosyloxy)-5-isopropyl-4-[(4-{3-[2-(methoxycarbonyl)ethylamino]propoxy}-2-methylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 using methyl 3-(2-nitrobenzenesulfonylamino)propionateinstead of 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.95-2.05 (2H, m), 2.29 (3H,s), 2.64 (2H, t, J=6.5 Hz), 2.75-2.85 (1H, m), 2.9-3.1 (4H, m), 3.25-3.4(4H, m), 3.6-3.7 (6H, m), 3.75-3.85 (1H, m), 4.03 (2H, t, J=6.0 Hz),5.0-5.05 (1H, m), 6.64 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.73 (1H, d, J=2.3Hz), 6.87 (1H, d, J=8.3 Hz)

Example 843-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-(2-[(4-methylpiperazin-1-yl)carbonyl]ethylamino}propoxy)-2-methylphenyl]methyl)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 using4-methyl-1-[3-(2-nitrobenzenesulfonylamino)propionyl]piperazine insteadof 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (6H, s),2.35-2.45 (4H, m), 2.6 (2H, t, J=6.6 Hz), 2.75-2.9 (5H, m), 3.3-3.4 (4H,m), 3.5-3.7 (7H, m), 3.8-3.85 (1H, m), 4.0 (2H, t, J=6.0 Hz), 5.0-5.05(1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.85(1H, d, J=8.4 Hz)

Example 853-(β-D-Glucopyranosyloxy)-4-({4-[3-(2-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl)ethylamino)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 using4-(2-acetoxyethyl)-1-[3-(2-nitrobenzenesulfonylamino)propionyl]piperazineinstead of 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.46 (2H, t, J=5.1 Hz), 2.5-2.55 (4H, m), 2.6 (2H, t, J=6.6 Hz),2.75-2.9 (5H, m), 3.25-3.4 (4H, m), 3.5-3.7 (9H, m), 3.75-3.85 (1H, m),4.0 (2H, t, J=6.0 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.6Hz), 6.72 (1H, d, J=2.6 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 863-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{2-[(piperazin-1-yl)carbonyl]ethylamino}propoxy)-2-methylphenyl]methyl}-1H-pyrazole

3-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-(2-[(4-benzylpiperazin-1-yl)carbonyl]ethylamino}propoxy)-2-methylphenyl]methyl}-1H-pyrazolewas prepared in a similar manner to that described in Example 51 using4-benzyl-1-[3-(2-nitrobenzenesulfonylamino)propionyl]piperazine insteadof 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide. Then the titlecompound was prepared in a similar manner to that described in Example79 using this material instead of4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.59 (2H, t, J=6.6 Hz), 2.7-2.9 (9H, m), 3.3-3.4 (4H, m), 3.45-3.55 (4H,m), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m), 4.0 (2H, t, J=6.0 Hz), 4.95-5.05(1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.3 Hz), 6.72 (1H, d, J=2.3 Hz), 6.85(1H, d, J=8.4 Hz)

Example 873-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-(2-hydroxyethylcarbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of 3-benzyloxycarbonylaminopropionic acid (1 g) intetrahydrofuran (10 mL) was added 1,1′-carbonylbis-1H-imidazole (0.94g), and the mixture was stirred at room temperature for 1 hour. To thereaction mixture was added 2-aminoethanol (0.81 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredinto water, and the resulting mixture was extracted with ethyl acetate.The extract was washed with 0.5 mol/L hydrochloric acid, water and brinesuccessively, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and the residue was washed with a mixedsolvent of n-hexane and ethyl acetate (2/1), and dried under reducedpressure to give 2-[3-(benzyloxycarbonylamino)propionylamino]ethanol(0.25 g). The obtained2-[3-(benzyloxycarbonylamino)propionylamino]-ethanol (50 mg) wasdissolved in methanol (3 mL). To the solution was added 10%palladium-carbon powder (20 mg), and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 2 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give 2-(3-aminopropionylamino)ethanol (24 mg).To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(0.81 g) and triethylamine (0.21 mL) in dichloromethane (6 mL) was addedmethanesulfonyl chloride (0.11 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(0.89 g). To a solution of the obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(50 mg) in acetonitrile (1 mL)-ethanol (1 mL) were added2-(3-aminopropionylamino)ethanol described above (23 mg) and sodiumiodide (11 mg), and the mixture was stirred at 60° C. for 3 days. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1-5/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-(2-hydroxyethylcarbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole(42 mg). This material was dissolved in methanol (3 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.03 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (18 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.41 (2H, t, J=6.7 Hz), 2.7-2.9 (5H, m), 3.25-3.4 (6H, m), 3.57 (2H, t,J=5.7 Hz), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.1 Hz),4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5Hz), 6.85 (1H, d, J=8.4 Hz)

Example 883-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-(3-hydroxypropylcarbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 87 using 3-amino-1-propanol instead of 2-aminoethanol.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.65-1.75 (2H, m), 1.9-2.0 (2H,m), 2.29 (3H, s), 2.4 (2H, t, J=6.8 Hz), 2.75-2.9 (5H, m), 3.24 (2H, t,J=6.9 Hz), 3.25-3.4 (4H, m), 3.56 (2H, t, J=6.3 Hz), 3.6-3.7 (3H, m),3.75-3.85 (1H, m), 3.99 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 893-(β-D-Glucopyranosyloxy)-4-{[4-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethylcarbamoyl]ethylamino)propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 87 using 2-amino-1,3-propanediol instead of 2-aminoethanol.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.44 (2H, t, J=6.7 Hz), 2.75-2.85 (3H, m), 2.88 (2H, t, J=6.7 Hz),3.25-3.4 (4H, m), 3.55-3.7 (7H, m), 3.75-3.85 (1H, m), 3.9-3.95 (1H, m),4.0 (2H, t, J=6.1 Hz), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5Hz), 6.71 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 903-(β-D-Glucopyranosyloxy)-4-{[4-(3-{2-[2-hydroxy-1-(hydroxymethyl)-1-(methyl)ethylcarbamoyl]ethylamino}-propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 87 using 2-amino-2-methyl-1,3-propanediol instead of2-aminoethanol.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.22 (3H, s), 1.9-2.0 (2H, m),2.29 (3H, s), 2.4 (2H, t, J=6.5 Hz), 2.75-2.9 (5H, m), 3.25-3.4 (4H, m),3.55-3.75 (7H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0 Hz), 4.95-5.05(1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.85(1H, d, J=8.4 Hz)

Example 913-(β-D-Glucopyranosyloxy)-4-{[4-(3-(2-[2-hydroxy-1,1-bis-(hydroxymethyl)ethylcarbamoyl]ethylamino}propoxy)-2-methylphenyl]methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 87 using tris(hydroxymethyl)-aminomethane instead of2-aminoethanol.

H-NMR (CD₃OD) δ ppm: 0.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.44 (2H, t, =6.4 Hz), 2.75-2.9 (5H, m), 3.25-3.4 (4H, m), 3.6-3.75 (9H,m), 0.75-3.85 (1H, m), 4.0 (2H, t, J=6.0 Hz), 4.95-5.05 (1H, m), 6.62(1H, dd, J=8.4 Hz, 2.2 Hz), 6.71 (1H, d, J=2.2 Hz), 6.85 (1H, d, J=8.4Hz)

Reference Example 473-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.81 (3H, s), 1.98 (3H, s),2.0-2.1 (5H, m), 2.22 (3H, s), 2.26 (3H, s), 2.75-2.85 (1H, m), 3.5 (1H,d, J=16.5 Hz), 3.55-3.7 (3H, m), 4.0-4.1 (3H, m), 4.1-4.2 (2H, m), 4.52(2H, s), 5.07 (1H, dd, J=10.3 Hz, 3.3 Hz), 5.35-5.45 (2H, m), 5.52 (1H,d, J=7.8 Hz), 6.58 (1H, dd, J=8.4 Hz, 2.7 Hz), 6.69 (1H, d, J=2.7 Hz),6.79 (1H, d, J=8.4 Hz), 7.2-7.35 (5H, m)

Reference Example 483-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 1.95-2.05 (8H, m),2.16 (3H, s), 2.27 (3H, s), 2.75-2.85 (1H, m), 3.51 (1H, d, J=16.6 Hz),3.61 (1H, d, J=16.6 Hz), 3.8-3.9 (2H, m), 4.0-4.2 (5H, m), 5.07 (1H, dd,J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.51 (1H, d, J=8.2 Hz), 6.6 (1H,dd, J=8.5 Hz, 2.7 Hz), 6.7 (1H, d, J=2.7 Hz), 6.81 (1H, d, J=8.5 Hz)

Reference Example 49 3-Benzylaminopropionamide

To a solution of acrylamide (32 g) in ethanol (450 mL) was addedbenzylamine (59 mL), and the mixture was stirred at 60 C.° overnight.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/1-dichloromethane/methanol=50/1) to give thetitle compound (73.2 g).

¹H-NMR (CDCl₃) δ ppm: 2.35-2.45 (2H, m), 2.9-2.95 (2H, m), 3.81 (2H, s),5.15-5.6 (1H, br), 7.2-7.65 (6H, m)

Example 923-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-(3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy)-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.1 g) and triethylamine (0.026 mL) in dichloromethane (3 mL) was addedmethanesulfonyl chloride (0.013 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(0.11 g). This material was dissolved in a solution of acetonitrile (2mL) and methanol (2 mL). To the solution were added3-benzylaminopropionamide (46 mg) and sodium iodide (24 mg), and themixture was stirred at 60° C. for 3 days. The reaction mixture waspoured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: dichloromethane/methanol=20/1-10/1) to give thetitle compound (78 mg).

H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.83 (3H, s), 1.9-2.0 (5H, m),2.02 (3H, s), 2.15 (3H, s), 2.26 (3H, s), 2.39 (2H, t, J=6.1 Hz), 2.67(2H, t, J=7.0 Hz), 2.7-2.85 (3H, m), 3.5 (1H, d, J=16.6 Hz), 3.55-3.65(3H, m), 3.91 (2H, t, J=6.1 Hz), 4.0-4.1 (1H, m), 4.1-4.2 (2H, m), 5.07(1H, dd, J=10.4 Hz, 3.5 Hz), 5.21 (1H, brs), 5.35-5.45 (2H, m), 5.53(1H, d, J=8.2 Hz), 6.53 (1H, dd, J=8.6 Hz, 2.4 Hz), 6.63 (1H, d, J=2.4Hz), 6.79 (1H, d, J=8.6 Hz), 7.2-7.35 (5H, m), 7.44 (1H, brs)

Example 933-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 92 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.15 (6H, m), 1.82 (3H, s), 1.9-2.1 (11H, m),2.25 (3H, s), 2.39 (2H, t, J=6.1 Hz), 2.66 (2H, t, J=7.2 Hz), 2.7-2.9(3H, m), 3.49 (1H, d, J=16.2 Hz), 3.58 (1H, d, J=16.2 Hz), 3.62 (2H, s),3.8-3.95 (3H, m), 4.05-4.15 (1H, m), 4.29 (1H, dd, J=12.2 Hz, 4.0 Hz),5.15-5.3 (4H, m), 5.56 (1H, d, J=7.6 Hz), 6.52 (1H, dd, J=8.2 Hz, 2.7Hz), 6.62 (1H, d, J=2.7 Hz), 6.79 (1H, d, J=8.2 Hz), 7.2-7.35 (5H, m),7.47 (1H, brs)

Example 944-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)-amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(75 mg) in methanol (3 mL) was added 10% palladium-carbon powder (20mg), and the mixture was stirred at room temperature under a hydrogenatmosphere for 2.5 hours. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure togive4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole(66 mg). This material was dissolved in methanol (3 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.03 mL), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added acetic acid (0.04 mL), and the resulting mixture wasconcentrated under reduced pressure. The residue was purified by solidphase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (43 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.28 (3H, s),2.42 (2H, t, J=6.8 Hz), 2.7-2.9 (5H, m), 3.49 (1H, dd, J=9.7 Hz, 3.2Hz), 3.55-3.8 (6H, m), 3.85 (1H, d, J=3.2 Hz), 3.99 (2H, t, J=6.1 Hz),5.0-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.7 (1H, d, J=2.5Hz), 6.85 (1H, d, J=8.4 Hz)

Example 954-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)-amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(45.3 g) in methanol (400 mL) was added sodium methoxide (28% methanolsolution, 2.2 mL), and the mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=5/1-4/1) to give the title compound (33.2 g).

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.28 (3H, s),2.4 (2H, t, J=6.9 Hz), 2.55-2.65 (2H, m), 2.75-2.85 (3H, m), 3.25-3.4(4H, m), 3.55-3.75 (5H, m), 3.75-3.85 (1H, m), 3.92 (2H, t, J=6.2 Hz),4.95-5.05 (1H, m), 6.55 (1H, dd, J=8.5 Hz, 2.8 Hz), 6.62 (1H, d, J=2.8Hz), 6.83 (1H, d, J=8.5 Hz), 7.15-7.35 (5H, m)

Reference Example 50 (4-Benzyloxy-2-methylphenyl)methanol

The title compound was prepared in a similar manner to that described inReference Example 9 using benzyl bromide instead of benzyl 3-bromopropylether.

¹H-NMR (CDCl₃) δ ppm: 1.37 (1H, t, J=5.8 Hz), 2.36 (3H, s), 4.64 (2H, d,J=5.8 Hz), 5.06 (2H, s), 6.79 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.84 (1H, d,J=2.4 Hz), 7.23 (1H, d, J=8.4 Hz), 7.25-7.45 (5H, m)

Reference Example 51[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol

To a solution of tetrahydro-4H-pyran-4-ol (3.62 g) and triethylamine(5.6 mL) in tetrahydrofuran (35 mL) was added methanesulfonyl chloride(2.93 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 1 hour. The insoluble material was removed byfiltration. To the filtrate were added N,N-dimethylformamide (70 mL),4-benzyloxy-2-hydroxybenzaldehyde (5.39 g) and cesium carbonate (23 g),and the mixture was stirred at 80° C. for 12 hours. The reaction mixturewas poured into water, and the resulting mixture was extracted withdiethyl ether. The extract was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give4-benzyloxy-2-(tetrahydro-4H-pyran-4-yl-oxy)benzaldehyde (4.58 g). Thismaterial was dissolved in ethanol (70 mL). To the solution was addedsodium borohydride (0.28 g) under ice-cooling, and the mixture wasstirred at room temperature for 3 hours. To the reaction mixture wasadded methanol, and the resulting mixture was concentrated under reducedpressure. A saturated aqueous sodium hydrogen carbonate solution wasadded to the residue, and the mixture was extracted with diethyl ether.The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine successively, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give the titlecompound (4.45 g).

¹H-NMR (CDCl₃) δ ppm: 1.75-1.85 (2H, m), 1.95-2.05 (2H, m), 2.11 (1H, t,J=6.3 Hz), 3.5-3.65 (2H, m), 3.9-4.0 (2H, m), 4.45-4.55 (1H, m), 4.63(2H, d, J=6.3 Hz), 5.05 (2H, s), 6.5-6.6 (2H, m), 7.19 (1H, d, J=7.7Hz), 7.3-7.45 (5H, m)

Reference Example 524-[(4-Benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using (4-benzyloxy-2-methylphenyl)methanol insteadof [4-(3-benzyloxypropoxy)-phenyl]methanol.

H-NMR (DMSO-d₆) δ ppm: 1.04 (6H, d, J=6.8 Hz), 2.24 (3H, s), 2.65-2.8(1H, m), 3.44 (2H, s), 5.02 (2H, s), 6.69 (1H, dd, J=8.7 Hz, 2.4 Hz),6.75-6.85 (2H, m), 7.25-7.45 (5H, m)

Reference Example 534-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methanol instead of[4-(3-benzyloxypropoxy)phenyl]methanol.

¹H-NMR (CDCl₃) δ ppm: 1.16 (6H, d, J=7.1 Hz), 1.75-1.9 (2H, m), 1.95-2.1(2H, m), 2.9-3.05 (1H, m), 3.5-3.6 (2H, m), 3.64 (2H, s), 3.9-4.05 (2H,m), 4.4-4.5 (1H, m), 5.0 (2H, s), 6.45-6.55 (2H, m), 7.0 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference Example 544-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.;Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.;Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.04 (9H, s), 1.05-1.2 (33H, m), 2.27 (3H, s),2.7-2.85 (1H, m), 3.45-3.6 (2H, m), 3.8-3.9 (1H, m), 4.11 (1H, dd,J=12.6 Hz, 4.8 Hz), 4.17 (1H, dd, J=12.6 Hz, 1.8 Hz), 5.0 (2H, s),5.15-5.3 (2H, m), 5.37 (1H, t, J=9.5 Hz), 5.65 (1H, d, J=7.8 Hz), 6.64(1H, dd, J=8.4 Hz, 2.8 Hz), 6.77 (1H, d, J=2.8 Hz), 6.83 (1H, d, J=8.4Hz), 7.25-7.45 (5H, m)

Reference Example 554-{[4-Benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide instead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.7-1.85 (2H, m), 1.95-2.05 (2H,m), 2.85-2.95 (1H, m), 3.5-3.65 (4H, m), 3.8-3.9 (1H, m), 3.9-4.0 (2H,m), 4.12 (1H, dd, J=12.4 Hz, 5.1 Hz), 4.19 (1H, dd, J=12.4 Hz, 1.8 Hz),4.4-4.5 (1H, m), 4.99 (2H, s), 5.15-5.3 (2H, m), 5.36 (1H, t, J=9.4 Hz),5.66 (1H, d, J=8.0 Hz), 6.42 (1H, dd, J=8.3 Hz, 2.3 Hz), 6.47 (1H, d,J=2.3 Hz), 6.86 (1H, d, J=8.3 Hz), 7.25-7.45 (5H, m)

Reference Example 561-(2-Benzyloxyethyl)-4-[(4-benzyloxy-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(2 g) in N,N-dimethylacetoamide (36 mL) were added sodium hydride (55%,0.26 g) and benzyl 2-bromoethyl ether (0.76 mL) under ice-cooling, andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was poured into water, and the resulting mixture was extractedwith diethylether The extract was washed with water twice and brine, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the titlecompound (0.89 g).

H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.28 (3H, s), 2.95-3.05 (1H, m),3.52 (1H, d, J=17.0 Hz), 3.57 (1H, d, J=17.0 Hz), 3.75-3.85 (3H, m),4.0-4.2 (4H, m), 4.46 (1H, d, J=12.1 Hz), 4.49 (1H, d, J=12.1 Hz), 4.99(2H, s), 5.1-5.2 (2H, m), 5.34 (1H, t, J=9.5 Hz), 5.61 (1H, d, J=8.1Hz), 6.6 (1H, dd, J=8.5 Hz, 2.6 Hz), 6.73 (1H, d, J=8.5 Hz), 6.77 (1H,d, J=2.6 Hz), 7.2-7.45 (10H, m)

Reference Example 574-[(4-Benzyloxy-2-methylphenyl)methyl]-1-(3-benzyloxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 56 using benzyl 3-bromopropyl ether instead of benzyl2-bromoethyl ether.

H-NMR (CDCl₃) δ ppm: 1.03 (9H, s), 1.05-1.2 (33H, m), 2.05-2.15 (2H, m),2.28 (3H, s), 2.9-3.0 (1H, m), 3.45-3.6 (4H, m), 3.7-3.8 (1H, m),3.95-4.1 (3H, m), 4.12 (1H, dd, J=12.0 Hz, 1.9 Hz), 4.51 (2H, s), 5.0(2H, s), 5.1-5.2 (2H, m), 5.33 (1H, t, J=9.5 Hz), 5.61 (1H, d, J=8.2Hz), 6.61 (1H, dd, J=8.3 Hz, 2.7 Hz), 6.72 (1H, d, J=8.3 Hz), 6.77 (1H,d, J=2.7 Hz), 7.2-7.5 (10H, m)

Reference Example 584-[(4-Hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(5 g) was dissolved in tetrahydrofuran (18 mL). To the solution wasadded 10% palladium-carbon powder (500 mg), and the mixture was stirredat room temperature under a hydrogen atmosphere for 3 hours. Theinsoluble material was removed by filtration, and the solvent of thefiltrate was removed under reduced pressure to give the title compound(4.45 g).

H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.24 (3H, s), 2.7-2.85 (1H, m),3.52 (2H, s), 3.8-3.9 (1H, m), 4.09 (1H, dd, J=12.4 Hz, 4.7 Hz), 4.15(1H, dd, J=12.4 Hz, 1.9 Hz), 4.6 (1H, s), 5.15-5.25 (2H, m), 5.36 (1H,t, J=9.2 Hz), 5.65 (1H, d, J=8.0 Hz), 6.5 (1H, dd, J=8.3 Hz, 2.9 Hz),6.61 (1H, d, J=2.9 Hz), 6.78 (1H, d, J=8.3 Hz)

Reference Example 591-(2-Hydroxyethyl)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 58 using1-(2-benzyloxyethyl)-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.26 (3H, s), 2.9-3.0 (1H, m),3.51 (1H, d, J=17.0 Hz), 3.55 (1H, d, J=17.0 Hz), 3.75-3.9 (2H, m),3.9-4.0 (2H, m), 4.0-4.15 (4H, m), 4.61 (1H, s), 5.15-5.25 (2H, m), 5.35(1H, t, J=9.4 Hz), 5.53 (1H, d, J=8.1 Hz), 6.48 (1H, dd, J=8.4 Hz, 2.7Hz), 6.61 (1H, d, J=2.7 Hz), 6.67 (1H, d, J=8.4 Hz)

Reference Example 604-[(4-Hydroxy-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 58 using4-[(4-benzyloxy-2-methylphenyl)methyl]-1-(3-benzyloxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

H-NMR (CDCl₃) δ ppm: 1.03 (9H, s), 1.05-1.15 (24H, m), 1.19 (9H, s),1.9-2.0 (2H, m), 2.25 (3H, s), 2.9-3.0 (1H, m), 3.5 (1H, d, J=17.3 Hz),3.54 (1H, d, J=17.3 Hz), 3.6-3.7 (2H, m), 3.8-3.9 (1H, m), 3.93 (1H, t,J=6.4 Hz), 4.1-4.2 (3H, m), 4.22 (1H, dd, J=12.6 Hz, 1.7 Hz), 4.51 (1H,s), 5.15-5.25 (2H, m), 5.35 (1H, t, J=9.4 Hz), 5.52 (1H, d, J=8.1 Hz),6.48 (1H, dd, J=8.3 Hz, 2.4 Hz), 6.61 (1H, d, J=2.4 Hz), 6.66 (1H, d,J=8.3 Hz)

Reference Example 614-{[4-Hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 58 using4-{[4-benzyloxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.9 (2H, m), 1.95-2.1 (2H,m), 2.8-2.95 (1H, m), 3.52 (1H, d, J=16.5 Hz), 3.55-3.65 (3H, m),3.8-3.9 (1H, m), 3.9-4.05 (2H, m), 4.05-4.2 (2H, m), 4.4-4.5 (1H, m),5.14 (1H, brs), 5.15-5.3 (2H, m), 5.3-5.4 (1H, m), 5.65 (1H, d, J=8.1Hz), 6.22 (1H, dd, J=8.2 Hz, 2.3 Hz), 6.37 (1H, d, J=2.3 Hz), 6.78 (1H,d, J=8.2 Hz)

Reference Example 624-{[4-(3-Chloropropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-[(4-hydroxy-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(8.58 g), 1-bromo-3-chloropropane (2.85 mL) and tetra(n-butyl)ammoniumbromide (1.86 g) in tetrahydrofuran (43 mL) was added 5 mol/L aqueoussodium hydroxide solution (5.76 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into 1 mol/Lhydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with 1 mol/L hydrochloric acid, water andbrine successively, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was dissolved inn-hexane (15 mL)-diisopropyl ether (5 mL) under reflux condition. Thesolution was cooled to room temperature, and n-hexane (25 mL) was addedto the solution. The precipitated crystals were collected by filtration,and the crystals were washed with n-hexane and dried under reducedpressure to give the title compound (6.06 g).

H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.15-2.25 (2H, m), 2.27 (3H, s),2.7-2.85 (1H, m), 3.51 (1H, d, J=16.7 Hz), 3.53 (1H, d, J=16.7 Hz), 3.73(2H, t, J=6.4 Hz), 3.8-3.9 (1H, m), 4.05 (2H, t, J=5.9 Hz), 4.11 (1H,dd, J=12.4 Hz, 4.7 Hz), 4.17 (1H, dd, J=12.4 Hz, 1.9 Hz), 5.15-5.3 (2H,m), 5.3-5.4 (1H, m), 5.65 (1H, d, J=8.1 Hz), 6.57 (1H, dd, J=8.4 Hz, 2.7Hz), 6.68 (1H, d, J=2.7 Hz), 6.83 (1H, d, J=8.4 Hz)

Reference Example 634-{[4-(3-Chloropropoxy)-2-methylphenyl]methyl}-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.69 g), 1-bromo-3-chloropropane (0.22 mL) and tetra(n-butyl)ammoniumbromide (0.14 g) in tetrahydrofuran (8 mL) was added 5 mol/L aqueoussodium hydroxide solution (0.43 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted withdiethylether. The extract was washed with water and brine successively,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) togive the title compound (0.56 g).

H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 2.15-2.25 (2H, m), 2.28 (3H, s),2.9-3.0 (1H, m), 3.52 (1H, d, J=16.9 Hz), 3.57 (1H, d, J=16.9 Hz), 3.73(2H, t, J=6.2 Hz), 3.75-4.0 (4H, m), 4.0-4.15 (6H, m), 5.15-5.25 (2H,m), 5.35 (1H, t, J=9.6 Hz), 5.54 (1H, d, J=8.1 Hz), 6.56 (1H, dd, J=8.5Hz, 2.5 Hz), 6.69 (1H, d, J=2.5 Hz), 6.72 (1H, d, J=8.5 Hz)

Reference Example 644-{[4-(3-Chloropropoxy)-2-methylphenyl]methyl}-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-[(4-hydroxy-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.02 (9H, s), 1.05-1.15 (24H, m), 1.19 (9H, s),1.9-2.0 (2H, m), 2.15-2.25 (2H, m), 2.28 (3H, s), 2.9-3.0 (1H, m), 3.51(1H, d, J=16.9 Hz), 3.55 (1H, d, J=16.9 Hz), 3.6-3.7 (2H, m), 3.73 (2H,t, J=6.3 Hz), 3.8-3.9 (1H, m), 3.96 (1H, t, J=6.4 Hz), 4.05 (2H, t,J=5.9 Hz), 4.1-4.2 (3H, m), 4.23 (1H, dd, J=12.6 Hz, 1.7 Hz), 5.15-5.25(2H, m), 5.35 (1H, t, J=9.4 Hz), 5.52 (1H, d, J=8.1 Hz), 6.55 (1H, dd,J=8.4 Hz, 2.6 Hz), 6.69 (1H, d, J=2.6 Hz), 6.71 (1H, d, J=8.4 Hz)

Reference Example 654-{[4-(3-Chloropropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 63 using4-{[4-hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.9 (2H, m), 2.0-2.1 (2H,m), 2.15-2.25 (2H, m), 2.85-2.95 (1H, m), 3.5-3.65 (4H, m), 3.73 (2H, t,J=6.4 Hz), 3.8-3.9 (1H, m), 3.9-4.1 (4H, m), 4.13 (1H, dd, J=12.4 Hz,4.8 Hz), 4.19 (1H, dd, J=12.4 Hz, 1.9 Hz), 4.4-4.55 (1H, m), 5.15-5.3(2H, m), 5.3-5.4 (1H, m), 5.66 (1H, d, J=8.1 Hz), 6.34 (1H, dd, J=8.4Hz, 2.4 Hz), 6.41 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)

Reference Example 663-[N-Benzyloxycarbonyl-N-(3-bromopropyl)amino]propionamide

To a solution of acrylamide (2 g) in ethanol (30 mL) was added3-amino-1-propanol (3.23 mL), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure. To the residue were added tetrahydrofuran (30 mL) andN-(benzyloxycarbonyloxy)-succinimide (14 g), and the mixture was stirredat room temperature overnight. The reaction mixture was poured intowater, and the resulting mixture was extracted with ethyl acetate. Theextract was washed with water and brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas purified by column chromatography on silica gel (eluent:dichloromethane/methanol=40/1-20/1-5/1) to give3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)-amino]propionamide (3.51 g).To a solution of the obtained3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl)amino]propionamide (0.5 g) andcarbon tetrabromide (0.65 g) in dichloromethane (5 mL) was addedtriphenylphosphine (1.03 g) under ice-cooling, and the mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto water, and the resulting mixture was extracted with ethyl acetate.The extract was washed with water and brine, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/4-dichloromethane/methanol=10/1) to give thetitle compound (0.41 g).

H-NMR (CD₃OD) δ ppm: 2.0-2.2 (2H, m), 2.4-2.55 (2H, m), 3.35-3.5 (4H,m), 3.56 (2H, t, J=6.9 Hz), 5.12 (2H, s), 7.25-7.45 (5H, m)

Example 964-[(4-{3-[N-Benzyloxycarbonyl-N-(2-carbamoylethyl)amino]-propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.4 g), 3-[N-benzyloxycarbonyl-N-(3-bromopropyl)amino]propionamide(0.28 g) and tetra(n-butyl)-ammonium bromide (87 mg) in dichloromethane(4 mL) was added 5 mol/L aqueous sodium hydroxide solution (0.32 mL),and the mixture was stirred at room temperature overnight. The reactionmixture was poured into 1 mol/L hydrochloric acid, and the resultingmixture was extracted with diethylether. The extract was washed with 1mol/L hydrochloric acid, water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/3-1/6) to give the title compound (0.42 g).

H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.9-2.05 (2H, m), 2.25 (3H, s),2.4-2.55 (2H, m), 2.75-2.85 (1H, m), 3.45-3.65 (6H, m), 3.85-4.0 (3H,m), 4.08 (1H, dd, J=12.5 Hz, 1.9 Hz), 4.16 (1H, dd, J=12.5 Hz, 4.4 Hz),4.95-5.2 (4H, m), 5.35-5.45 (1H, m), 5.58 (1H, d, J=7.9 Hz), 6.45-6.75(2H, m), 6.8 (1H, d, J=8.4 Hz), 7.25-7.4 (5H, m)

Example 974-{[4-{3-[N-Benzyloxycarbonyl-N-(2-carbamoylethyl)amino]-propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 96 using4-{[4-hydroxy-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.7-1.85 (2H, m), 1.9-2.15 (4H,m), 2.4-2.55 (2H, m), 2.85-2.95 (1H, m), 3.35-3.65 (8H, m), 3.85-4.0(5H, m), 4.11 (1H, dd, J=12.5 Hz, 1.9 Hz), 4.18 (1H, dd, J=12.5 Hz, 4.4Hz), 4.45-4.6 (1H, m), 5.05-5.2 (4H, m), 5.35-5.4 (1H, m), 5.57 (1H, d,J=8.2 Hz), 6.2-6.6 (2H, m), 6.8 (1H, d, J=8.4 Hz), 7.2-7.45 (5H, m)

Example 984-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

A mixture of4-{[4-(3-chloropropoxy)-2-methylphenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.34 g), 3-benzylaminopropionamide (0.73 g), sodium iodide (0.24 g),ethanol (6 mL) and acetonitrile (6 mL) was stirred at 70° C. for 2 days.To the reaction mixture was added sodium iodide (0.2 g), and the mixturewas further stirred at 75° C. for 24 hours. The reaction mixture waspoured into 1 mol/L hydrochloric acid, and the resulting mixture wasextracted with ethylacetate. The extract was washed with water, asaturated aqueous sodium hydrogen carbonate solution and brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethylacetate=1/5-dichloromethane/methanol=15/1) to give the title compound(0.97 g).

¹H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.85-1.95 (2H, m), 2.26 (3H, s),2.4 (2H, t, J=6.9 Hz), 2.62 (2H, t, J=6.9 Hz), 2.75-2.9 (3H, m), 3.52(1H, d, J=16.4 Hz), 3.56 (1H, d, J=16.4 Hz), 3.62 (2H, s), 3.85-3.95(3H, m), 4.08 (1H, dd, J=12.4 Hz, 1.8 Hz), 4.16 (1H, dd, J=12.4 Hz, 4.4Hz), 5.05-5.2 (2H, m), 5.35-5.45 (1H, m), 5.58 (1H, d, J=8.1 Hz), 6.52(1H, dd, J=8.5 Hz, 2.5 Hz), 6.61 (1H, d, J=2.5 Hz), 6.79 (1H, d, J=8.5Hz), 7.15-7.35 (5H, m)

Example 994-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 98 using4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.85-1.95 (2H, m), 2.28 (3H, s),2.4 (2H, t, J=7.1 Hz), 2.62 (2H, t, J=7.0 Hz), 2.8 (2H, t, J=7.1 Hz),3.05-3.15 (1H, m), 3.5-3.65 (4H, m), 3.8-3.95 (5H, m), 4.0-4.2 (4H, m),5.0-5.2 (2H, m), 5.36 (1H, t, J=9.5 Hz), 5.59 (1H, d, J=7.8 Hz), 6.5(1H, dd, J=8.5 Hz, 2.7 Hz), 6.62 (1H, d, J=2.7 Hz), 6.7 (1H, d, J=8.5Hz), 7.15-7.4 (5H, m)

Example 1004-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 98 using4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.85-2.05 (4H, m), 2.28 (3H, s),2.4 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=7.0 Hz), 2.8 (2H, t, J=7.0 Hz),3.0-3.1 (1H, m), 3.5-3.65 (6H, m), 3.85-3.95 (3H, m), 4.0-4.2 (4H, m),5.0-5.2 (2H, m), 5.37 (1H, t, J=9.4 Hz), 5.6 (1H, d, J=7.7 Hz), 6.5 (1H,dd, J=8.4 Hz, 2.6 Hz), 6.62 (1H, d, J=2.6 Hz), 6.67 (1H, d, J=8.4 Hz),7.15-7.35 (5H, m)

Example 1014-{[4-{3-[1-Carbamoyl-1-(methyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 98 using4-{[4-(3-chloropropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleand 2-amino-2-methylpropionamide instead of4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleand 3-benzylaminopropionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (42H, m), 1.32 (6H, s), 1.7-1.85 (2H, m),1.85-2.1 (4H, m), 2.69 (2H, t, J=7.0 Hz), 2.85-2.95 (1H, m), 3.53 (1H,d, J=16.6 Hz), 3.55-3.7 (3H, m), 3.85-4.05 (5H, m), 4.11 (1H, dd, J=12.4Hz, 1.6 Hz), 4.18 (1H, dd, J=12.4 Hz, 4.3 Hz), 4.55-4.65 (1H, m),5.05-5.2 (2H, m), 5.3-5.4 (1H, m), 5.56 (1H, d, J=8.2 Hz), 6.38 (1H, dd,J=8.4 Hz, 2.2 Hz), 6.53 (1H, d, J=2.2 Hz), 6.81 (1H, d, J=8.4 Hz)

Example 1024-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.96 g) in tetrahydrofuran (5 mL) was added 10% palladium-carbon powder(0.1 g), and the mixture was stirred at room temperature under ahydrogen atmosphere overnight. The insoluble material was removed byfiltration, and the filtrate was concentrated under reduced pressure togive the title compound (0.87 g).

H-NMR (CD₃OD) δ ppm: 1.05-1.2 (42H, m), 1.9-2.0 (2H, m), 2.27 (3H, s),2.43 (2H, t, J=6.8 Hz), 2.75-2.9 (5H, m), 3.53 (1H, d, J=16.4 Hz), 3.56(1H, d, J=16.4 Hz), 3.9-4.05 (3H, m), 4.08 (1H, dd, J=12.4 Hz, 1.8 Hz),4.16 (1H, dd, J=12.4 Hz, 4.4 Hz), 5.05-5.2 (2H, m), 5.35-5.45 (1H, m),5.58 (1H, d, J=8.1 Hz), 6.59 (1H, dd, J=8.4 Hz, 2.6 Hz), 6.7 (1H, d,J=2.6 Hz), 6.81 (1H, d, J=8.4 Hz)

Example 1034-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 102 using4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (42H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.42 (2H, t, J=6.9 Hz), 2.77 (2H, t, J=7.1 Hz), 2.85 (2H, t, J=6.9 Hz),3.05-3.2 (1H, m), 3.56 (1H, d, J=16.8 Hz), 3.61 (1H, d, J=16.8 Hz),3.8-4.2 (9H, m), 5.0-5.2 (2H, m), 5.37 (1H, t, J=9.4 Hz), 5.59 (1H, d,J=8.0 Hz), 6.56 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.65-6.75 (2H, m)

Example 1044-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 102 using4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.9-2.05 (4H, m), 2.29 (3H, s),2.44 (2H, t, J=6.8 Hz), 2.81 (2H, t, J=7.1 Hz), 2.88 (2H, t, J=6.8 Hz),3.0-3.15 (1H, m), 3.5-3.65 (4H, m), 3.85-4.2 (7H, m), 5.0-5.2 (2H, m),5.37 (1H, t, J=9.5 Hz), 5.6 (1H, d, J=8.4 Hz), 6.57 (1H, dd, J=8.3 Hz,2.3 Hz), 6.65-6.75 (2H, m)

Example 1054-{[4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 102 using4-{[4-(3-[N-benzyloxycarbonyl-N-(2-carbamoylethyl)amino]propoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.0-1.2 (42H, m), 1.7-1.85 (2H, m), 2.0-2.1 (2H,m), 2.1-2.2 (2H, m), 2.67 (2H, t, J=6.2 Hz), 2.85-2.95 (1H, m), 3.2-3.35(4H, m), 3.54 (1H, d, J=16.5 Hz), 3.55-3.7 (3H, m), 3.9-4.0 (3H, m),4.05-4.15 (3H, m), 4.19 (1H, dd, J=12.4 Hz, 4.4 Hz), 4.55-4.65 (1H, m),5.05-5.2 (2H, m), 5.35-5.45 (1H, m), 5.58 (1H, d, J=8.1 Hz), 6.43 (1H,dd, J=8.4 Hz, 2.3 Hz), 6.64 (1H, d, J=2.3 Hz), 6.84 (1H, d, J=8.4 Hz)

Example 1064-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-1-(3-hydroxypropyl)-5-isopropyl-1H-pyrazole

To a solution of4-[(4-{3-[2-(carbamoyl)ethylamino]-propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.3 g) in methanol (6 mL) was added sodium methoxide (28% methanolsolution, 0.25 mL), and the mixture was stirred at 50 C.° overnight. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent: methanol) to give the title compound (0.16 g).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.9-2.05 (4H, m), 2.3 (3H, s),2.42 (2H, t, J=6.8 Hz), 2.77 (2H, t, J=7.1 Hz), 2.84 (2H, t, J=6.8 Hz),3.0-3.15 (1H, m), 3.2-3.4 (4H, m), 3.55-3.75 (5H, m), 3.8 (1H, dd,J=12.1 Hz, 2.1 Hz), 3.99 (2H, t, J=6.2 Hz), 4.11 (2H, t, J=7.2 Hz), 5.03(1H, d, J=7.6 Hz), 6.6 (1H, dd, J=8.3 Hz, 2.6 Hz), 6.72 (1H, d, J=2.6Hz), 6.74 (1H, d, J=8.3 Hz)

Example 1074-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-1-(2-hydroxyethyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 106 using4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-1-(2-hydroxyethyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (6H, m), 1.85-2.0 (2H, m), 2.3 (3H, s),2.41 (2H, t, J=6.8 Hz), 2.77 (2H, t, J=7.1 Hz), 2.84 (2H, t, J=6.8 Hz),3.05-3.2 (1H, m), 3.2-3.4 (4H, m), 3.6-3.75 (3H, m), 3.79 (1H, dd,J=12.0 Hz, 2.2 Hz), 3.85 (2H, t, J=5.7 Hz), 3.99 (2H, t, J=6.0 Hz), 4.09(2H, t, J=5.7 Hz), 5.06 (1H, d, J=7.7 Hz), 6.6 (1H, dd, J=8.4 Hz, 2.7Hz), 6.72 (1H, d, J=2.7 Hz), 6.77 (1H, d, J=8.4 Hz)

Example 1084-{[4-{3-[1-Carbamoyl-1-(methyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 106 using4-{[4-{3-[1-carbamoyl-1-(methyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.29 (6H, s), 1.7-1.85 (2H, m),1.85-1.95 (2H, m), 1.95-2.1 (2H, m), 2.64 (2H, t, J=6.9 Hz), 2.8-2.95(1H, m), 3.25-3.45 (4H, m), 3.55-3.75 (5H, m), 3.8-3.9 (1H, m), 3.9-4.05(4H, m), 4.5-4.65 (1H, m), 5.0-5.1 (1H, m), 6.4 (1H, dd, J=8.4 Hz, 2.0Hz), 6.53 (1H, d, J=2.0 Hz), 6.9 (1H, d, J=8.4 Hz)

Example 1094-{[4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 106 using4-{[4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-{3-[2-(carbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.7-1.85 (2H, m), 1.9-2.1 (4H,m), 2.43 (2H, t, J=6.8 Hz), 2.79 (2H, t, J=7.0 Hz), 2.8-2.95 (3H, m),3.25-3.4 (4H, m), 3.55-3.75 (5H, m), 3.8-3.85 (1H, m), 3.9-4.05 (4H, m),4.55-4.65 (1H, m), 5.0-5.1 (1H, m), 6.41 (1H, dd, J=8.4 Hz, 2.4 Hz),6.54 (1H, d, J=2.4 Hz), 6.9 (1H, d, J=8.4 Hz)

Example 1104-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1.25 g) in methanol (13 mL) was added sodium methoxide (28% methanolsolution, 0.25 mL), and the mixture was stirred at 50 C.° for 6 hours.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1-5/1) to give the title compound (0.5 g).

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.28 (3H, s),2.4 (2H, t, J=6.9 Hz), 2.55-2.65 (2H, m), 2.75-2.85 (3H, m), 3.25-3.4(4H, m), 3.55-3.75 (5H, m), 3.75-3.85 (1H, m), 3.92 (2H, t, J=6.2 Hz),4.95-5.05 (1H, m), 6.55 (1H, dd, J=8.5 Hz, 2.8 Hz), 6.62 (1H, d, J=2.8Hz), 6.83 (1H, d, J=8.5 Hz), 7.15-7.35 (5H, m)

Example 1114-[(4-{3-[2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

4-[(4-{3-[N-Benzyl-N-(2-carbamoylethyl)amino]-propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(0.5 g) was dissolved in methanol (8 mL). To the solution was added 10%palladium-carbon powder (0.1 g), and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 3 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure. A part (0.1 g) of the residue was dissolved in amixed solvent of methanol (1 mL) and ethyl acetate (1.5 mL). To thesolution was added a seed crystal, and the mixture was stirred at roomtemperature for 3 days. The precipitated crystals were collected byfiltration. The crystals were washed with a mixed solvent of methanoland ethyl acetate (⅔), and dried under reduced pressure to give thetitle compound (85 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.29 (3H, s),2.42 (2H, t, J=6.9 Hz), 2.7-2.9 (5H, m), 3.25-3.4 (4H, m), 3.6-3.75 (3H,m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.2 Hz), 4.95-5.05 (1H, m), 6.62(1H, dd, J=8.4 Hz, 2.4 Hz), 6.71 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.4Hz) melting point: 191-193° C.

Example 1124-[(4-{(S)-3-[2-(Carbamoyl)ethylamino]-2-hydroxypropoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a suspension of4-[(4-hydroxy-2-methylphenyl)-methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.3 g) and potassium carbonate (84 mg) in N,N-dimethylformamide (3 mL)were added (S)-1-(p-toluenesulfonyloxy)-2,3-epoxypropane (0.1 g) and acatalytic amount of cesium fluoride, and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into a saturatedaqueous ammonium chloride solution, and the resulting mixture wasextracted with ethyl acetate. The extract was washed with a saturatedaqueous sodium hydrogen carbonate solution and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was dissolved in methanol (5 mL). To thesolution was added 3-benzylaminopropionamide (0.14 g), and the mixturewas stirred at 50 C.° overnight. The reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethylacetate=1/2-dichloromethane/methanol=10/1) to give4-[(4-{(S)-3-[N-benzyl-N-(2-carbamoylethyl)amino]-2-hydroxypropoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.23 g). This material was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (0.1 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 4 days.The insoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inmethanol (5 mL). To the solution was added sodium methoxide (28%methanol solution, 0.085 mL), and the mixture was stirred at 50 C.°overnight. The reaction mixture was concentrated under reduced pressure,and the residue was purified by solid phase extraction on ODS (washingsolvent: distilled water, eluent: methanol) and preparative reversephase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120Å, 20×50 mm, flow rate 30 mL/minute linear gradient,water/methanol=90/10-10/90) successively to give the title compound (23mg).

¹H-NMR (CD₃OD) δ ppm: 0.05-1.15 (6H, m), 2.29 (3H, s), 2.43 (2H, t,J=6.7 Hz), 2.65-2.95 (5H, m), 3.25-3.4 (4H, m), 3.6-3.7 (3H, m),3.75-3.85 (1H, m), 3.9 (2H, d, J=5.3 Hz), 3.95-4.05 (1H, m), 4.95-5.05(1H, m), 6.64 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.74 (1H, d, J=2.4 Hz), 6.86(1H, d, J=8.4 Hz)

Example 1134-[(4-{(R)-3-[2-(Carbamoyl)ethylamino]-2-hydroxypropoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 112 using (R)-1-(p-toluenesulfonyloxy)-2,3-epoxypropane insteadof (S)-1-(p-toluenesulfonyloxy)-2,3-epoxypropane.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.43 (2H, t,J=6.7 Hz), 2.65-2.95 (5H, m), 3.25-3.4 (4H, m), 3.6-3.7 (3H, m),3.75-3.85 (1H, m), 3.9 (2H, d, J=5.3 Hz), 4.0-4.05 (1H, m), 4.95-5.05(1H, m), 6.64 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.74 (1H, d, J=2.5 Hz), 6.86(1H, d, J=8.4 Hz)

Reference Example 67 Benzyl 3-benzylaminopropionate

To a solution of benzyl acrylate (2 g) in ethanol (15 mL) was addedbenzylamine (1.75 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and the residue was purified by column chromatography on silica gel(eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound(2.91 g).

¹H-NMR (CDCl₃) δ ppm: 2.59 (2H, t, J=6.5 Hz), 2.92 (2H, t, J=6.5 Hz),3.79 (2H, s), 5.13 (2H, s), 7.2-7.4 (10H, m)

Example 1144-{[4-{3-[2-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]ethylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(1 g) and triethylamine (0.29 mL) in dichloromethane (10 mL) was addedmethanesulfonyl chloride (0.13 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(1.12 g). This material was dissolved in acetonitrile (7 mL)-ethanol (7mL). To the solution were added benzyl 3-benzylaminopropionate (1.27 g)and sodium iodide (240 mg), and the mixture was stirred at 60 C.° for 2days. The reaction mixture was poured into water, and the resultingmixture was extracted with ethylacetate. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: dichloromethane/methanol30/1-20/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-benzyloxycarbonylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(1.3 g). This material was dissolved in methanol (10 mL). To thesolution was added 10% palladium-carbon powder (0.65 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere overnight.The insoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(2-carboxyethylamino)-propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole(0.95 g). This material was dissolved in 1,4-dioxane (10 mL). To thesolution were added sodium hydrogen carbonate (0.45 g) and water (10mL), and the mixture was stirred for 15 minutes. To the reaction mixturewas added benzyloxycarbonyl chloride (0.23 mL), and the mixture wasstirred at room temperature overnight. To the reaction mixture was addedbenzyloxycarbonyl chloride (0.23 mL), and the mixture was stirred atroom temperature for 3 hours. The reaction mixture was poured into 0.5mol/L hydrochloric acid, and the resulting mixture was extracted withethyl acetate. The extract was washed with water and brine, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-[3-[N-benzyloxycarbonyl-N-(2-carboxyethyl)amino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole(0.86 g). To a solution of the obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyloxycarbonyl-N-(2-carboxyethyl)amino]-propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(0.17 g) in N,N-dimethylformamide (3 mL) were added L-serine amidehydrochloride (37 mg), 1-hydroxybenzotriazole (30 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg) andtriethylamine (0.11 mL), and the mixture was stirred at room temperaturefor 8 hours. The reaction mixture was poured into water, and theresulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1-10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N-benzyloxycarbonyl-N-{2-[(S)-1-carbamoyl-2-hydroxyethylcarbamoyl]ethyl}amino)propoxy]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole(81 mg). This material was dissolved in methanol (5 mL). To the solutionwas added 10% palladium-carbon powder (10 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 3 hours. Theinsoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inmethanol (4 mL). To the solution was added sodium methoxide (28%methanol solution, 0.02 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by solid phase extractionon ODS (washing solvent: distilled water, eluent: methanol) to give thetitle compound (38 mg).

H-NMR (CD₃OD) δ ppm: 1.0-1.2 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H, s),2.4-2.55 (2H, m), 2.7-2.95 (5H, m), 3.25-3.4 (4H, m), 3.55-3.85 (6H, m),3.99 (2H, t, J=6.1 Hz), 4.35-4.45 (1H, m), 4.95-5.05 (1H, m), 6.61 (1H,dd, J=8.4 Hz, 2.2 Hz), 6.71 (1H, d, J=2.2 Hz), 6.84 (1H, d, J=8.4 Hz)

Example 1154-[(4-{3-[2-(Carbamoylmethylcarbamoyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 114 using glycinamide hydrochloride instead of L-serine amidehydrochloride.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.29 (3H, s),2.46 (2H, t, J=6.6 Hz), 2.7-2.85 (3H, m), 2.88 (2H, t, J=6.6 Hz),3.3-3.4 (4H, m), 3.6-3.7 (3H, m), 3.75-3.85 (3H, m), 3.99 (2H, t, J=6.1Hz), 5.0-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d,J=2.5 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 1164-{[4-(3-(2-[(S)-1-(Carbamoyl)ethylcarbamoyl]ethylamino}-propoxy)-2-methylphenyl]methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 114 using L-alanine amide hydrochloride instead of L-serineamide hydrochloride.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.33 (3H, d, J=7.2 Hz), 1.9-2.0(2H, m), 2.29 (3H, s), 2.35-2.5 (2H, m), 2.7-2.9 (5H, m), 3.3-3.4 (4H,m), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.1 Hz), 4.32(1H, q, J=7.2 Hz), 4.95-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.3 Hz),6.71 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 1174-{[4-(3-{2-[(S)-5-Amino-1-(carbamoyl)pentylcarbamoyl]-ethylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 114 using (S)-2-amino-6-(benzyloxycarbonylamino)hexanamidehydrochloride instead of L-serine amide hydrochloride.

H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.25-2.0 (8H, m), 2.29 (3H, s),2.35-2.55 (2H, m), 2.63 (2H, t, J=7.0 Hz), 2.7-2.95 (5H, m), 3.25-3.4(4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0 Hz),4.25-4.35 (1H, m), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.2 Hz),6.71 (1H, d, J=2.2 Hz), 6.84 (1H, d, J=8.4 Hz)

Reference Example 68 Benzyl 3-amino-2,2-di(methyl)propionate

To a solution of 3-amino-2,2-dimethyl-1-propanol (5 g) in methanol (50mL) was added di-tert-butyl dicarbonate (12.7 g), and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure. The residue (solid) was treatedwith n-hexane-diethyl ether and collected by filtration, washed withn-hexane and dried under reduced pressure to give3-(tert-butoxycarbonylamino)-2,2-dimethyl-1-propanol (7.48 g). To thismaterial were added carbon tetrachloride (40 mL), acetonitrile (40 mL),water (48 mL), sodium periodate (38.8 g) and ruthenium trichloride-nhydrate (1 g) successively, and the mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with water, andthe resulting mixture was extracted with ethyl acetate.

The organic layer was washed with water and brine. To the organic layerwas added a saturated aqueous potassium carbonate solution, and theaqueous layer was separated. The aqueous layer was acidified with 2mol/L hydrochloric acid, and the mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure to give 3-(tert-butoxycarbonylamino)-2,2-di(methyl)propionicacid (2.78 g). This material was dissolved in N,N-dimethylformamide (30mL). To the solution were added potassium carbonate (3.54 g) and benzylbromide (2.28 mL), and the mixture was stirred at room temperatureovernight. The reaction mixture was poured into water, and the resultingmixture was extracted with ethylacetate. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1)to give benzyl 3-(tert-butoxycarbonylamino)-2,2-di(methyl)propionate(2.72 g). To this material was added hydrochloric acid (4 mol/L1,4-dioxane solution, 10 mL), and the mixture was stirred at roomtemperature for 3 days. The reaction mixture was concentrated underreduced pressure. To the residue was added a saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give the title compound (1.61 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.09 (6H, s), 1.35-1.7 (2H, br), 2.63 (2H, s),5.09 (2H, s), 7.25-7.45 (5H, m)

Example 1183-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{2-[(piperazin-1-yl)carbonyl]-2-(methyl)propylamino}propoxy)-2-methylphenyl]methyl}-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(1 g) and triethylamine (0.25 mL) in dichloromethane (5 mL) was addedmethanesulfonyl chloride (0.13 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured into 0.5 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(1.12 g). The obtained3-(2,3,4,6-tetra-O-acetyl-(β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole(0.36 g) was dissolved in 2-propanol (2 mL)-acetonitrile (2 mL). To thesolution were added benzyl 3-amino-2,2-di-(methyl)propionate (0.26 g)and sodium iodide (75 mg), and the mixture was stirred at 60 C.° for 2days. The reaction mixture was poured into water, and the resultingmixture was extracted with ethyl acetate. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent: n-hexane/ethylacetate=1/5-dichloromethane/methanol=20/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-benzyloxycarbonyl-2-(methyl)propylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(0.35 g). This material was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (0.1 g), and the mixturewas stirred at room temperature under a hydrogen atmosphere for 5 hours.The insoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[2-carboxy-2-(methyl)propylamino]propoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole(0.31 g). This material was dissolved in tetrahydrofuran (4 mL). To thesolution were added triethylamine (0.094 mL) andN-(benzyloxycarbonyloxy)-succinimide (64 mg), and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 0.5 mol/L hydrochloric acid, and the resulting mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=20/1) togive3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-{N-benzyloxycarbonyl-N-[2-carboxy-2-(methyl)propyl]amino}propoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.3 g). To a solution of the obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-(N-benzyloxycarbonyl-N-[2-carboxy-2-(methyl)-propyl]amino}propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(0.1 g) in N,N-dimethylformamide (2 mL) were added 1-benzylpiperazine(26 mg), 1-hydroxybenzotriazole (17 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg) andtriethylamine (0.064 mL), and the mixture was stirred at roomtemperature for 6 hours. The reaction mixture was poured into water, andthe resulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=40/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-(N-benzyloxycarbonyl-N-[2-(4-benzylpiperazin-1-yl)carbonyl-2-(methyl)propyl]amino)propoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(45 mg). This material was dissolved in tetrahydrofuran (4 mL). To thesolution was added 10% palladium-carbon powder (20 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere overnight.To the reaction mixture was added methanol (2 mL), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 5 hours. Theinsoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inmethanol (2 mL). To the solution was added sodium methoxide (28%methanol solution, 0.02 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was purified by solid phase extractionon ODS (washing solvent: distilled water, eluent: methanol) andpreparative reverse phase column chromatography (Shiseido CAPCELL PAKUG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute lineargradient, water/methanol=90/10-10/90) successively to give the titlecompound (12 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.29 (6H, s), 1.85-2.0 (2H, m),2.3 (3H, s), 2.65-2.9 (9H, m), 3.25-3.4 (4H, m), 3.5-3.75 (7H, m),3.75-3.85 (1H, m), 4.0 (2H, t, J=5.8 Hz), 5.0-5.1 (1H, m), 6.62 (1H, dd,J=8.4 Hz, 2.0 Hz), 6.72 (1H, d, J=2.0 Hz), 6.84 (1H, d, J=8.4 Hz)

Example 1194-{[4-(3-{2-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]-2-(methyl)propylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 118 using L-serine amide hydrochloride instead of1-benzylpiperazine.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.17 (3H, s), 1.19 (3H, s),1.9-2.0 (2H, m), 2.28 (3H, s), 2.7 (2H, s), 2.75-2.85 (3H, m), 3.25-3.4(4H, m), 3.6-3.7 (3H, m), 3.76 (1H, dd, J=11.1 Hz, 4.7 Hz), 3.8-3.9 (2H,m), 4.0 (2H, t, J=6.1 Hz), 4.35-4.4 (1H, m), 4.95-5.05 (1H, m), 6.61(1H, dd, J=8.4 Hz, 2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 6.84 (1H, d, J=8.4Hz)

Example 1203-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{2-[(4-methylpiperazin-1-yl)carbonyl]-2-(methyl)propylamino}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 118 using 1-methylpiperazine instead of 1-benzylpiperazine.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.29 (6H, s), 1.85-2.0 (2H, m),2.26 (3H, s), 2.29 (3H, s), 2.3-2.45 (4H, m), 2.6-2.85 (5H, m), 3.25-3.4(4H, m), 3.55-3.75 (7H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0 Hz),4.95-5.05 (1H, m), 6.61 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.71 (1H, d, J=2.5Hz), 6.84 (1H, d, J=8.4 Hz)

Example 1213-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-2-(methyl)propylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 118 using 1-(2-hydroxyethyl)-piperazine instead of1-benzylpiperazine.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.29 (6H, s), 1.85-2.0 (2H, m),2.29 (3H, s), 2.4-2.55 (6H, m), 2.65-2.85 (5H, m), 3.25-3.4 (4H, m),3.55-3.75 (9H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=5.8 Hz), 5.0-5.05(1H, m), 6.61 (1H, dd, J=8.3 Hz, 1.9 Hz), 6.71 (1H, d, J=1.9 Hz), 6.85(1H, d, J=8.3 Hz)

Reference Example 69 Benzyl 3-amino-3-methylbutyrate

To a suspension of 3,3-dimethylacrylic acid (1.3 g) and potassiumcarbonate (2.07 g) in N,N-dimethylformamide (15 mL) was added benzylbromide (1.19 mL), and the mixture was stirred at room temperature for 4hours. The reaction mixture was poured into water, and the resultingmixture was extracted with diethyl ether. The extract was washed withwater and brine, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was dissolved in2-propanol (20 mL). An ammonia gas was bubbled into the solution at −15C.° until saturation, and the mixture was stirred at 80 C.° overnight.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=15/1-7/1) to give the title compound (0.31 g).

H-NMR (DMSO-d₆) δ ppm: 1.08 (6H, s), 1.78 (2H, brs), 2.38 (2H, s), 5.08(2H, s), 7.3-7.4 (5H, m)

Example 1223-(β-D-Glucopyranosyloxy)-4-[(4-{3-[2-{[4-(2-hydroxyethyl)-piperazin-1-yl]carbonyl}-1,1-di(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

A mixture of4-{[4-(3-chloropropoxy)-2-methylphenyl]-methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(1 g) and sodium iodide (0.27 g) in acetonitrile (5 mL) was heated forreflux for 10 hours. After cooling to 60 C.°, to the reaction mixturewas added a solution of benzyl 3-amino-3-methylbutyrate (0.31 g) in2-propanol (5 mL), and the mixture was stirred at 55 C.° for 6 days. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate-water. The organic layer wasseparated. The organic layer was washed with water and brine, and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane/ethylacetate=1/2-dichloromethane/methanol=20/1) to give4-[(4-{3-[2-benzyloxycarbonyl-1,1-di(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.63 g). This material was dissolved in methanol (5 mL). To thesolution was added 10% palladium-carbon powder (65 mg), and the mixturewas stirred at room temperature under a hydrogen atmosphere overnight.The insoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give4-[(4-{3-[2-carboxy-1,1-di(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.52 g). To a solution of4-[(4-{3-[2-carboxy-1,1-di(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.1 g) in N,N-dimethylformamide (2 mL) were added1-(2-hydroxyethyl)piperazine (19 mg), 1-hydroxybenzotriazole (17 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg) andtriethylamine (0.062 mL), and the mixture was stirred at roomtemperature for 20 hours. The reaction mixture was poured into water,and the resulting mixture was extracted with ethyl acetate. The extractwas washed with water and brine, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas dissolved in methanol (3 mL). To the solution was added sodiummethoxide (28% methanol solution, 0.1 mL), and the mixture was stirredat 50 C.° overnight. The reaction mixture was concentrated under reducedpressure, and the residue was purified by solid phase extraction on ODS(washing solvent: distilled water, eluent: methanol) and preparativereverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient,water/methanol=90/10-10/90) successively to give the title compound (13mg).

MS(ESI, m/z): 678 [M+H]⁺

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.18 (6H, s), 1.85-2.0 (2H, m),2.29 (3H, s), 2.42 (2H, t, J=5.0 Hz), 2.45-2.55 (6H, m), 2.71 (2H, t,J=7.0 Hz), 2.75-2.9 (1H, m), 3.25-3.4 (4H, m), 3.5-3.75 (9H, m),3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0 Hz), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 1234-{[4-(3-{2-[(S)-1-Carbamoyl-2-hydroxyethylcarbamoyl]-1,1-di(methyl)ethylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 122 using L-serine amide hydrochloride instead of1-(2-hydroxyethyl)piperazine.

MS(ESI, m/z): 652 [M+H]⁺

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.19 (6H, s), 1.85-2.0 (2H, m),2.2-2.5 (5H, m), 2.7-2.95 (3H, m), 3.25-3.4 (4H, m), 3.55-3.9 (6H, m),4.01 (2H, t, J=6.1 Hz), 4.35-4.45 (1H, m), 4.95-5.05 (1H, m), 6.62 (1H,dd, J=8.3 Hz, 2.3 Hz), 6.72 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=8.3 Hz)

Example 1244-{[4-(3-{2-[(S)-5-Amino-1-(carbamoyl)pentylcarbamoyl]-1,1-di(methyl)ethylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

4-{[4-(3-{2-[(S)-5-Benzyloxycarbonylamino-1-(carbamoyl)pentylcarbamoyl]-1,1-di(methyl)ethylamino}-propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazolewas prepared in a similar manner to that described in Example 122 using2-amino-6-(benzyloxycarbonylamino)hexanamide hydrochloride instead of1-(2-hydroxyethyl)piperazine, and the title compound was prepared in asimilar manner to that described in Example 79 using this materialinstead of4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole.

MS(ESI, m/z): 693 [M+H]⁺

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.17 (6H, s), 1.25-1.85 (6H,m), 1.85-2.0 (2H, m), 2.2-2.45 (5H, m), 2.55-2.9 (5H, m), 3.25-3.4 (4H,m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.02 (2H, t, J=5.8 Hz),4.25-4.35 (1H, m), 4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.4 Hz, 2.3 Hz),6.72 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=8.4 Hz)

Example 1253-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{2-[(piperazin-1-yl)carbonyl]-1,1-di(methyl)ethylamino}-propoxy)-2-methylphenyl]methyl}-1H-pyrazole

4-{[4-(3-{2-[(4-Benzylpiperazin-1-yl)carbonyl]-1,1-di(methyl)ethylamino}propoxy)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazolewas prepared in a similar manner to that described in Example 122 using1-benzylpiperazine instead of 1-(2-hydroxyethyl)piperazine, and thetitle compound was prepared in a similar manner to that described inExample 79 using this material instead of4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole.

MS(ESI, m/z): 634 (M+H]⁺

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.19 (6H, s), 1.85-2.0 (2H, m),2.29 (3H, s), 2.52 (2H, s), 2,6-2.9 (7H, m), 3.25-3.4 (4H, m), 3.4-3.55(4H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 3.99 (2H, t, J=6.0 Hz),4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.4 Hz, 2.5 Hz), 6.72 (1H, d, J=2.5Hz), 6.84 (1H, d, J=8.4 Hz)

Reference Example 70 3-Aminobutyramide

To a mixture of 3-aminobutyric acid (0.52 g), 2 mol/L aqueous sodiumhydroxide solution (10 mL) and tetrahydrofuran (10 mL) was addedbenzyloxycarbonyl chloride (1.07 mL), and the mixture was stirred atroom temperature overnight. The reaction mixture was poured into 2 mol/Lhydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure. The residue (solid) was treated with n-hexane. The crystalswere collected by filtration, washed with n-hexane and dried underreduced pressure to give 3-benzyloxycarbonylaminobutyric acid (0.59 g).This material was dissolved in tetrahydrofuran (5 mL). To the solutionwas added 1,1′-carbonylbis-1H-imidazole (0.59 g), and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture wasadded 28% aqueous ammonia solution (5 mL), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withdiethylether. The insoluble material was collected by filtration, washedwith water and diethyl ether, and dried under reduced pressure to give3-benzyloxycarbonylaminobutyramide (0.54 g). The obtained3-benzyloxycarbonylaminobutyramide (76 mg) was dissolved in methanol (3mL). To the solution was added 10% palladium-carbon powder (20 mg), andthe mixture was stirred at room temperature under a hydrogen atmospherefor 2 hours. The insoluble material was removed by filtration, and thefiltrate was concentrated under reduced pressure to give the titlecompound (32 mg).

¹H-NMR (CD₃OD) δ ppm: 0.14 (3H, d, J=6.6 Hz), 2.2-2.35 (2H, m),3.25-3.35 (1H, m)

Reference Example 71 3-Amino-2-methylpropionamide

The title compound was prepared in a similar manner to that described inReference Example 70 using 3-amino-2-methylpropionic acid instead of3-aminobutyric acid.

¹H-NMR (CD₃OD) δ ppm: 1.13 (3H, d, J=6.9 Hz), 2.4-2.5 (1H, m), 2.6-2.7(1H, m), 2.8-2.9 (1H, m)

Reference Example 72 3-Amino-2,2-di(methyl)propionamide

To a solution of 3-amino-2,2-dimethyl-1-propanol (2 g) intetrahydrofuran (20 mL) was added N-(benzyloxycarbonyloxy)-succinimide(7.25 g), and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethyl acetate. The extract was washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) togive 3-benzyloxycarbonylamino-2,2-dimethyl-1-propanol (4.6 g) To thismaterial were added carbon tetrachloride (40 mL), acetonitrile (40 mL),water (48 mL), sodium periodate (11.6 g) and ruthenium trichloride (0.2g) successively, and the mixture was stirred at room temperatureovernight. To the reaction mixture were added sodium periodate (11.6 g)and ruthenium trichloride (0.2 g), and the mixture was stirred at roomtemperature for 3 days. The reaction mixture was diluted with water, andthe resulting mixture was extracted with ethyl acetate. The extract wasdried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was dissolved in a saturated aqueouspotassium carbonate solution. The solution was washed with ethylacetate, and the aqueous layer was acidified with 2 mol/L hydrochloricacid. The mixture was extracted with ethyl acetate, and the extract waswashed with water and brine, and dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure to give3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid (3.6 g). Thismaterial was dissolved in tetrahydrofuran (25 mL). To the solution wasadded 1,1′-carbonylbis-1H-imidazole (3.39 g), and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture wasadded 28% aqueous ammonia solution (25 mL), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withwater, and the resulting mixture was extracted with ethyl acetate. Theextract was washed with 1 mol/L hydrochloric acid, water and brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to give3-benzyloxycarbonylamino-2,2-di(methyl)-propionamide (3.35 g). Theobtained 3-benzyloxycarbonylamino-2,2-di(methyl)propionamide (0.13 g)was dissolved in methanol (5 mL). To the solution was added 10%palladium-carbon powder (30 mg), and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 2 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (61 mg).

¹H-NMR (DMSO-d₆) δ ppm: 1.0 (6H, s), 1.4-2.0 (2H, br), 2.52 (2H, s),6.69 (1H, brs), 7.36 (1H, brs)

Examples 126-137

The compounds described in Tables 1-2 were prepared in a similar mannerto that described in Example 57 or Example 72 using the correspondingstarting materials. TABLE 1 Example No. Structure ¹H-NMR (CD₃OD) δ ppm:Example 126

1.05-1.2 (9H, m), 1.9-2.0 (2H, m), 2.25 (1H, dd, J=14.6Hz, 6.5Hz), 2.29(3H, s), 2.39 (1H, dd, J=14.6Hz, 6.5Hz), 2.7-2.9 (3H, m), 3.05-3.15 (1H,m), 3.25-3.4 (4H, m), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m), 4.0 (2H, t,J=6.0Hz),4.95-5.05(1H,m), 6.62 (1H, dd, J=8.4Hz, 2.3Hz), 6.71 (1H, # d,J=2.3Hz), 6.85 (1H, d, J=8.4Hz) Example 127

1.05-1.2 (9H, m), 1.9-2.0 (2H, m), 2.29 (3H, s), 2.5-2.65 (2H, m),2.7-2.9 (4H, m), 3.25-3.4 (4H, m), 3.6-3.7 (3H, m), 3.75-3.85 (1H, m),3.95-4.05 (2H, m), 4.95-5.05 (1H, m), 6.62 (1H, dd, J=8.3Hz, 2.3Hz),6.71 (1H, d, J=2.3Hz), 6.85 (1H, d, J=8.3Hz) Example 128

1.05-1.15 (6H, m), 1.17 (6H, s), 1.9-2.0 (2H, m), 2.29 (3H, a), 2.66(2H, s), 2.75-2.85 (3H, m), 3.25-3.4 (4H, m), 3.6-3.7 (3H, m), 3.75-3.85(1H, m), 4.0 (2H, t, J=6.0Hz), 4.95-5.05 (1H, m), 6.61 (1H, dd, J=8.4Hz,2.6Hz). 6.7 (1H, d, J=2.6Hz), 6.85 (1H, d, J=8.4Hz) Example 129

1.05-1.15 (6H, m), 1.16 (6H, s), 1.85-2.0 (2H, m), 2.28 (3H, s), 2.65(2H, s), 2.7-2.85 (3H, m), 3.49 (1H, dd, J=9.7Hz, 3.2Hz), 3.55-3.8 (6H,m), 3.85 (1H, d, J=3.2Hz), 3.99 (2H, t, J=6.0Hz), 5.03 (1H, d, J=7.9Hz),6.61 (1H, dd, J=8.4Hz, 2.3Hz). 6.7 (1H, d, J=2.3Hz), 6.85 (1H, d,J=8.4Hz) Example 130

1.05-1.2 (6H, m), 1.29 (6H, s), 1.85-1.95 (2H, m) , 2.28 (3H, s), 2.65(2H, t, J=7.0Hz), 2.75-2.85(1H, m), 3.49 (1H, dd, J=9.7Hz, 3.2Hz),3.55-3.8 (6H, m), 3.84 (1H, d, J=3.2Hz), 4.01 (2H, t, J=6.1Hz), 5.03(1H, d, J=7.7Hz), 6.61 (1H, dd, J=8.4Hz, 2.4Hz), 6.7 (1H, d, # J=2.4Hz),6.85 (1H, d, J=8.4Hz) Example 131

1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.28 (3H, s), 2.65-2.85 (5H, m),3.49 (1H, dd, J=9.8Hz, 3.6Hz), 3.55-3.8 (8H, m), 3.8-3.9 (1H, m), 3.99(2H, t, J=6.1Hz), 5.03 (1H, d, J=7.9Hz), 6.61 (1H, dd, J=8.4Hz, 2.6Hz),6.71 (1H, d. J=2.6Hz), 6.85 (1H, d, J=8.4Hz)

TABLE 2 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 132

1.03 (3H, d, 3=6.4Hz), 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H,s), 2.65-2.95 (4H, m), 3.38 (1H, dd, J=10.6Hz, 7.3Hz), 3.45-3.8 (8H, m),3.84 (1H, d, J=3.3Hz), 3.9-4.1 (2H, m), 5.03 (1H, d, J=8.0Hz), 6.61 (1H,dd, J=8.5Hz, 2.6Hz), 6.71(1H, d, 3=2.6Hz), 6.85 (1H, d, J=8.5Hz) Example133

1.05-1.15 (6H, m), 1.65-1.8(2H, m), 1.9-2.0 (2H, m), 2.28 (3H, s),2.65-2.85 (5H, m), 3.49 (1H, dd, J=9.7Hz, 3.5Hz), 3.55-3.8(8H, m), 3.84(1H, d, J=3.5Hz), 3.99 (2H, J=6.3Hz), 5.03 (1H, d, J=7.8Hz), 6.61 (1H,dd, J=8.5Hz. 2.7Hz), 6.7 (1H, d, J=2.7Hz), 6.85 (1H, d, J=8.5Hz) Example134

1.05-1.15 (6H, m), 1.9-2.0 (2H, m), 2.28 (3H, s), 2.65-2.9 (4H, m),3.45-3.8(11H, m), 3.8-3.9(1H, m), 4.0 (2H, t, J=6.1Hz), 5.03 (1H, d,J=7.8Hz), 6.61 (1H, dd, J=8.4Hz, 2.7Hz), 6.71(1H, d, J=2.7Hz), 6.84 (1H,d, J=8.4Hz) Example 135

0.99 (3H, s), 1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.28 (3H, s),2.7-2.85 (3H, m), 3.46 (4H, s), 3.49 (1H, dd, J=9.6Hz, 3.1Hz), 3.55-3.8(6H, m), 3.84 (1H, d, J=3.1Hz), 4.0 (2H, t, J=6.1Hz), 5.03 (1H, d,J=7.9Hz), 6.61 (1H, dd, J=8.3Hz, 2.6Hz), 6.71(1H, d, J=2.6Hz), 6.84 #1H, d, J=8.3Hz) Example 136

1.04 (6H, s), 1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H, s),2.65-2.85 (3H, m), 3.36 (2H, s), 3.49 (1H, dd, J=9.8Hz, 3.6Hz), 3.55-3.8(6H, m), 3.8-3.9 (1H, m), d, J=7.8Hz), 6.61(1H, dd, J=8.3Hz, 2.4Hz),6.71(1H, d, J=2.4Hz), 6.85 (1H, d, J=8.3Hz) Example 137

1.05-1.15 (6H, m), 1.85-2.0 (2H, m), 2.28 (3H, s), 2.7-2.9 (3H, m), 4.01(2H, t, J=6.1Hz), 5.03 (1H, d, J=7.8Hz), 6.61(1H, dd, J=8.6Hz, 2.4Hz),6.71(1H, d, J=2.4Hz), 6.85 (1H, d, J=8.6Hz)

Reference Example 733-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-azidopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 29 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.2 (6H, m), 1.82 (3H, s), 1.95-2.1 (8H, m),2.16 (3H, s), 2.27 (3H, s), 2.75-2.85 (1H, m), 3.45-3.55 (3H, m), 3.61(1H, d, J=16.3 Hz), 3.95-4.1 (3H, m), 4.1-4.2 (2H, m), 5.07 (1H, dd,J=10.4 Hz, 3.5 Hz), 5.35-5.45 (2H, m), 5.52 (1H, d, J=8.2 Hz), 6.58 (1H,dd, J=8.3 Hz, 2.6 Hz), 6.69 (1H, d, J=2.6 Hz), 6.81 (1H, d, J=8.3 Hz)

Reference Example 744-{[4-(3-Azidopropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a solution of4-{[4-(3-chloropropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole(0.3 g) in N,N-dimethylformamide (5 mL) was added sodium azide (43 mg),and the mixture was stirred at 80 C.° for 3 hours. To the reactionmixture was added water, and the precipitated crystals were collected byfiltration. The crystals were washed with water and n-hexane, and driedunder reduced pressure to give the title compound (0.3 g).

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.9 (2H, m), 1.95-2.1 (4H,m), 2.85-2.95 (1H, m), 3.45-3.65 (6H, m), 3.8-3.9 (1H, m), 3.95-4.05(4H, m), 4.1-4.25 (2H, m), 4.4-4.55 (1H, m), 5.15-5.3 (2H, m), 5.36 (1H,t, J=9.2 Hz), 5.67 (1H, d, J=8.0 Hz), 6.33 (1H, dd, J=8.5 Hz, 2.4 Hz),6.4 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.5 Hz)

Example 1383-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-azidopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.84 (3H, s), 1.85-2.0 (8H, m),2.14 (3H, s), 2.27 (3H, s), 2.75-2.9 (3H, m), 3.53 (1H, d, J=16.5 Hz),3.59 (1H, d, J=16.5 Hz), 4.0 (2H, t, J=6.2 Hz), 4.05-4.2 (3H, m),5.1-5.2 (1H, m), 5.2-5.3 (1H, m), 5.35-5.45 (2H, m), 6.61 (1H, dd, J=8.3Hz, 2.3 Hz), 6.71 (1H, d, J=2.3 Hz), 6.78 (1H, d, J=8.3 Hz)

Example 1394-{[4-(3-Aminopropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)-phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 1 using4-{[4-(3-azidopropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-azidopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.0-1.2 (42H, m), 1.75-1.95 (4H, m), 1.95-2.1 (2H,m), 2.8-3.0 (3H, m), 3.5-3.7 (4H, m), 3.8-3.9 (1H, m), 3.9-4.05 (4H, m),4.05-4.25 (2H, m), 4.4-4.55 (1H, m), 5.15-5.3 (2H, m), 5.36 (1H, t,J=9.3 Hz), 5.67 (1H, d, J=7.4 Hz), 6.3-6.45 (2H, m), 6.85 (1H, d, J=8.6Hz)

Example 1403-(β-D-Glucopyranosyloxy)-4-{[4-(2-{3-[2-hydroxy-1,1-bis-(hydroxymethyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{([4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(60 mg) in dichloromethane (3 mL) were added triethylamine (0.016 mL)and 4-nitrophenyl chloroformate (21 mg), and the mixture was stirred atroom temperature for 1 hour. To the reaction mixture were addedtris(hydroxymethyl)-aminomethane (35 mg) and methanol (3 mL), and themixture was stirred at room temperature for 3 hours. The reactionmixture was poured into water, and the resulting mixture was extractedwith ethyl acetate. The organic layer was washed with water and brine,and dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1-6/1)to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{([4-(2-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]ureido}ethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(36 mg). This material was dissolved in methanol (2 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.018 mL), and themixture was stirred at room temperature for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (22 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.29 (3H, s), 2.75-2.85 (1H,m), 3.25-3.4 (4H, m), 3.44 (2H, t, J=5.3 Hz), 3.6-3.75 (9H, m), 3.81(1H, d, J=11.7 Hz), 3.95 (2H, t, J=5.3 Hz), 5.02 (1H, d, J=6.6 Hz), 6.63(1H, dd, J=8.5 Hz, 2.4 Hz), 6.73 (1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.5Hz)

Examples 141-151

The compounds described in Tables 3-4 were prepared in a similar mannerto that described in Example 140 using the corresponding startingmaterials. The synthesis of Example 151 was carried out by catalytichydrogenation in a similar manner to that described in Example 79 afterthe completion of the operation of Example 140. TABLE 3 Example No.Structure ¹H-NMR (CD₃OD) δ ppm: Example 141

1.05-1.15 (6H, m), 1.85-1.95(2H, m), 2.29 (3H, s), 2.75-2.85 (1H, m),3.2-3.4 (6H, m), 3.6-3.75 (9H, m), 3.81 (1H, d, J=11.5Hz), 3.9-4.0 (2H,m), 4.95-5.05 (1H, m), 6.62 (1H, d, J=8.3Hz), 6.71 (1H, s), 6.85 (1H, d,J=8.3Hz) Example 143

1.05-1.15 (6H, m), 1.85-1.95 (2H, m), 2.28 (3H, s), 2.75-2.85 (1H, m),3.25 (2H, t, J=6.9Hz), 3.49 (1H, dd, J=9.8Hz, 3.3Hz). 3.55-3.8 (12H, m),3.8-3.9 (1H, m), 3.96 (2H, t, J=6.1Hz), 5.03(1H, d, J=7.8Hz), 6.61 (1H,dd, J=8.4Hz, 2.6Hz), 6.71 (1H, d, J=2.6Hz), 6.85 (1H, d, J=8.4Hz)Example 143

1.05-1.15(9H, m), 1.85-1.95(2H, m), 2.28 (3H, s), 2.75-2.85 (1H, m),3.2-3.5 (8H, m), 3.55-3.85 (5H, m), 3.96(2H, t, J=6.1Hz), 4.95-5.05(1H,m), 6.62 (1H, dd, J=8.4Hz, 2.5Hz), 6.71 (1H, d, J=2.5Hz), 6.86 (1H, d,J=8.4Hz) Example 144

1.05-1.15 (6H, m), 1.27 (6H, d), 2.29 (3H, s), 2.7-2.85 (1H, m), 2.89(3H, s), 3.2-3.4 (6H, m), 3.42 (2H, t, J=5.3Hz), 3.55-3.75 (3H, m),J=5.3Hz), 4.95-5.1(1H, m), 6.63(1H, dd, J=8.2Hz, 2.7Hz), 6.72 (1H, d,J=2.7Hz), 6.86 (1H, d, J=8.2Hz)

TABLE 4 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 145

1.05-1.15 (6H, m), 2.26 (6H, s), 2.29 (3H, s), 2.43 (2H, J=6.8Hz),2.75-2.85(1H, m), 3.2-3.4(6H, m), 3.46 (2H, t, J=5.4Hz), 3.6-3.75 (3H,m), 3.75-3.85 (1H, m), 3.95 (2H, t, J=5.4Hz), 4.95-5.05 (1H, m), 6.62(1H, dd, J=8.4Hz, 2.7Hz), 6.72 (1H, d, J=2.7Hz), 6.86 (1H, d, J=8.4Hz)Example 146

1.05-1.15 (6H, m), 1.6-1.7 (2H, m), 2.23 (6H, s), 2.29 (3H, s), 2.3-2.4(2H, m), 2.75-2.85 (1H, m), 3.14 (2H, t, J=7.0Hz), 3.25-3.4 (4H, m),3.46 (2H, t, J=5.4Hz), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 3.95 (2H, t,J=5.4Hz), 4.95-5.05 (1H, m), 6.63 (1H, dd, J=8.4Hz, 2.6Hz), # 6.72 (1H,d, J=2.6Hz), 6.86 (1H, d, J=8.4Hz) Example 147

0.91 (3H, d, J=6.6Hz), 0.96 (3H, d, J=6.5 Hz), 1.05-1.15 (6H, m),1.85-1.95 (2H, m), 2.0-2.1 (1H, m), 2.28 (3H, s), 2.75-2.85 (1H, m),3.25-3.4(6H, m), 3.6-3.75(3H, m), 3.81 (1H, d, J=12.4Hz), 3.97 (2H, t,J=6.2Hz), 4.06 (1H, d, J=6.1Hz), 5.02 (1H, d, J=7.0 Hz), 6.62 (1H, #5.02 (1H, d, J=7.0 Hz), 6.62 (1H, dd, J=8.3Hz, 2.4Hz), 6.72 (1H, d,J=2.4Hz), 6.85 (1H, d, J=8.3Hz) Example 148

1.05-1.15 (6H, m), 1.23 (6H, s), 1.8-1.95 (2H, m), 2.28 (3H, s),2.7-2.85 (1H, m), 3.24 (2H, t, J=6.9Hz), 3.4-3.8 (9H, m), 3.84 (1H, d,J=2.9Hz), 3.95 (2H, t, J=6.2Hz), 5.03 (1H, d, J=7.6Hz), 6.61(1H, dd,J=8.3Hz, 2.6Hz), 6.71 (1H, d, J=2.6Hz), 6.85 (1H, d, J=8.3Hz) Example149

1.05-1.2 (6H, m), 1.7-1.85 (2H, m) 1.85-1.95 (2H, m), 1.95-2.1 (2H, m),2.34 (6H, s), 2.52 (2H, t, J=6.5Hz), 2.8-2.95 (1H, m), 3.2-3.4(8H, m),3.55-3.75(5H, m), 3.83 (1H, d, J=12.0Hz), 3.9-4.0 (4H, m), 4.5-4.65(1H,m), 5.06(1H, d, J=7.0Hz), 6.41 (1H, dd, J=8.2Hz, # 2.4Hz), 6.53 (1H, d,J=2.4Hz), 6.9 (1H, d, J=8.2Hz) Example 150

1.05-1.2 (6H, m), 1.23 (6H, s), 1.7-1.95(4H, m), 1.95-2.1(2H, m),2.8-2.95 (1H, m), 3.24 (2H, t, J=6.8Hz), 3.25-3.4 (4H, m), 3.5 (2H, s),3.55-3.75 (5H, m), 3.83 (1H, d, J=11.1 Hz), 3.9-4.0 (4H, m), 4.5-4.65(1H, m), 5.0-5.1(1H, m), 6.41 (1H, dd, J=8.5Hz, 2.3Hz), # 6.54 (1H, d,J=2.3Hz), 6.9 (1H, d, J=8.5Hz) Example 151

1.05-1.15 (6H, m), 1.23 (6H, s), 2.29 (3H, s), 2.75-2.85 (3H, m),3.25-3.4 (4H, m), 3.42 (2H, t, J=5.4Hz), 3.6-3.75 (3H, m), 3.75-3.85(1H, m), 3.94 (2H, t, J=5.4Hz), 5.01 (1H, d, J=7.2Hz), 6.63(1H, dd,J=8.3Hz, 2.7Hz), 6.72 (1H, d, J=2.7Hz), 6.86 (1H, d, J=8.3Hz)

Reference Example 75 4-(2-Benzyloxyethyl)-1-bromobenzene

To a suspension of sodium hydride (60%, 1.09 g) in 1,2-dimethoxyethane(25 mL) was added 2-(4-bromophenyl)ethanol (5 g) under ice-cooling, andthe mixture was stirred at room temperature for 1.5 hours. To thereaction mixture was added benzyl bromide (3.25 mL), and the mixture wasstirred at 80 C.° overnight. To the reaction mixture was added asaturated aqueous ammonium chloride solution, and the resulting mixturewas extracted with diethyl ether. The extract was washed with water andbrine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: n-hexane-n-hexane/ethylacetate=50/1-20/1) to give the title compound (6.8 g).

H-NMR (CDCl₃) δ ppm: 2.86 (2H, t, J=6.8 Hz), 3.66 (2H, t, J=6.8 Hz), 4.5(2H, s), 7.05-7.15 (2H, m), 7.2-7.35 (5H, m), 7.35-7.45 (2H, m)

Reference Example 76 [4-(2-Benzyloxyethyl)phenyl]methanol

To a solution of 4-(2-benzyloxyethyl)-1-bromobenzene (6.8 g) intetrahydrofuran (80 mL) was added n-butyl lithium (2.6 mol/L n-hexanesolution, 8.98 mL) at −78° C. under an argon atmosphere, and the mixturewas stirred for 30 minutes. To the reaction mixture was addedN,N-dimethylformamide (20 mL), and the mixture was allowed to warm to 0°C. and stirred for 2 hours. The reaction mixture was poured into asaturated aqueous ammonium chloride solution, and the resulting mixturewas extracted with ethylacetate. The organic layer was washed with waterand brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure to give 4-(2-benzyloxyethyl)benzaldehyde(5.6 g). This material was dissolved in methanol (80 mL). To thesolution was added sodium borohydride (1.77 g) under ice-cooling, andthe mixture was stirred at room temperature overnight. To the reactionmixture was added a saturated aqueous ammonium chloride solution, andthe resulting mixture was extracted with diethyl ether. The organiclayer was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue (solid) was treated with n-hexane, collected by filtrationand dried under reduced pressure to give the title compound (5.41 g).

H-NMR (CDCl₃) δ ppm: 2.93 (2H, t, J=7.1 Hz), 3.68 (2H, t, J=7.1 Hz),4.52 (2H, s), 4.65 (2H, s), 7.15-7.4 (9H, m)

Reference Example 774-{[4-(2-Benzyloxyethyl)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using [4-(2-benzyloxyethyl)phenyl]methanol insteadof [4-(3-benzyloxypropoxy)phenyl]methanol.

¹H-NMR (DMSO-d₆) δ ppm: 1.07 (6H, d, J=7.1 Hz), 2.75-2.9 (3H, m), 3.54(2H, s), 3.59 (2H, t, J=6.9 Hz), 4.45 (2H, s), 7.0-7.15 (4H, m),7.2-7.35 (5H, m)

Reference Example 783-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(2-benzyloxyethyl)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.83 (3H, s), 2.01 (3H, s), 2.03(3H, s), 2.05 (3H, s), 2.8-2.95 (3H, m), 3.55-3.7 (4H, m), 3.8-3.9 (1H,m), 4.14 (1H, dd, J=12.5 Hz, 2.4 Hz), 4.31 (1H, dd, J=12.5 Hz, 3.9 Hz),4.5 (2H, s), 5.15-5.3 (3H, m), 5.5-5.6 (1H, m), 7.0-7.1 (4H, m),7.2-7.35 (5H, m)

Reference Example 793-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-benzyloxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-{[4-(2-benzyloxyethyl)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.1-1.2 (6H, m), 1.85 (3H, s), 1.99 (3H, s), 2.02(3H, s), 2.17 (3H, s), 2.85-2.95 (3H, m), 3.61 (1H, d, J=15.9 Hz), 3.65(2H, t, J=7.2 Hz), 3.69 (1H, d, J=15.9 Hz), 4.0-4.25 (3H, m), 4.51 (2H,s), 5.09 (1H, dd, J=10.6 Hz, 3.3 Hz), 5.4-5.5 (2H, m), 5.55 (1H, d,J=8.2 Hz), 7.0-7.1 (4H, m), 7.2-7.35 (5H, m)

Reference Example 803-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-benzyloxyethyl)-phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.18 (6H, d, J=7.2 Hz), 1.87 (3H, s), 2.0 (3H, s),2.02 (3H, s), 2.05 (3H, s), 2.81 (2H, t, J=6.6 Hz), 2.85-3.0 (1H, m),3.62 (1H, d, J=16.0 Hz), 3.67 (1H, d, J=16.0 Hz), 3.75-3.9 (3H, m), 4.12(1H, dd, J=12.4 Hz, 2.4 Hz), 4.29 (1H, dd, J=12.4 Hz, 3.8 Hz), 5.15-5.3(3H, m), 5.57 (1H, d, J=7.5 Hz), 7.05-7.15 (4H, m)

Reference Example 813-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-hydroxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 23 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(2-benzyloxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazoleinstead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole.

¹H-NMR (CDCl₃) δ ppm: 1.15-1.2 (6H, m), 1.88 (3H, s), 1.98 (3H, s), 2.02(3H, s), 2.17 (3H, s), 2.81 (2H, t, J=6.4 Hz), 2.85-3.0 (1H, m), 3.63(1H, d, J=16.1 Hz), 3.7 (1H, d, J=16.1 Hz), 3.8-3.9 (2H, m), 4.0-4.1(1H, m), 4.1-4.2 (2H, m), 5.08 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.35-5.45(2H, m), 5.56 (1H, d, J=8.1 Hz), 7.05-7.15 (4H, m)

Example 1524-{[4-(2-{3-[(S)-1-Carbamoyl-2-(methyl)propyl]ureido}-ethyl)phenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(2.13 g) and triethylamine (0.65 mL) in dichloromethane (20 mL) wasadded methanesulfonyl chloride (0.36 mL) under ice-cooling, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas poured into water, and the resulting mixture was extracted withethyl acetate. The extract was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-{[4-(2-methanesulfonyloxyethyl)phenyl]methyl}-1H-pyrazole(2.4 g). This material was dissolved in N,N-dimethylformamide (20 mL).To the solution was added sodium azide (0.71 g), and the mixture wasstirred at 80 C. ° for 3 hours. The reaction mixture was poured intowater, and the resulting mixture was extracted with ethyl acetate. Theextract was washed with water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure, andthe residue was purified by column chromatography on silica gel (eluent:n-hexane/ethyl acetate=1/1-1/2) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(1.55 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-azidoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(1 g) was dissolved in tetrahydrofuran (5 mL). To the solution was added10% palladium-carbon powder (0.15 g), and the mixture was stirred atroom temperature under a hydrogen atmosphere for 6 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(0.96 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-phenyl]methyl}-5-isopropyl-1H-pyrazole(0.48 g) was dissolved in dichloromethane (5 mL). To the solution wereadded triethylamine (0.13 mL) and 4-nitrophenyl chloroformate (0.18 g)under ice-cooling, and the mixture was stirred at room temperature for 2hours. A ⅙ amount of the reaction mixture was separated. To the part ofthe reaction mixture were added triethylamine (0.084 mL), L-valine amidehydrochloride (45 mg) and tetrahydrofuran (1 mL), and the mixture wasstirred at room temperature for 5 hours. The reaction mixture waspurified by column chromatography on silica gel (eluent: ethylacetate-ethyl acetate/methanol=10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-{3-[(S)-1-carbamoyl-2-(methyl)propyl]ureido}ethyl)phenyl]methyl}-5-isopropyl-1H-pyrazole(48 mg). This material was dissolved in methanol (2 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.013 mL), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added acetic acid (0.2 mL). The resulting mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (29 mg).

¹H-NMR (CD₃OD) δ ppm: 0.9 (3H, d, J=7.0 Hz), 0.95 (3H, d, J=6.5 Hz),1.1-1.2 (6H, m), 2.0-2.1 (1H, m), 2.71 (2H, t, J=7.1 Hz), 2.85-3.0 (1H,m), 3.25-3.45 (6H, m), 3.6-3.75 (2H, m), 3.78 (1H, d, J=16.0 Hz),3.8-3.9 (1H, m), 4.04 (1H, d, J=5.9 Hz), 5.04 (1H, d, J=7.4 Hz),7.05-7.15 (4H, m)

Examples 153-172

The compounds described in Tables 5-8 were prepared in a similar mannerto that described in Example 152 using the corresponding startingmaterials. The syntheses of Examples 171 and 172 were carried out bycatalytic hydrogenation in a similar manner to that described in Example79 after the completion of the operation of Example 152. TABLE 5 ExampleNo. Structure ¹H-NMR (CD₃OD) δ ppm: Example 153

1.1-1.2 (6H, m), 2.71 (2H, t, J=7.0Hz), 2.85-3.0 (1H, m), 3.2-3.4 (6H,m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.05-7.2 (4H, m) Example 154

1.1-1.2 (6H, m), 2.71 (2H, t, J=7.1Hz), 2.85-3.0 (1H, m), 3.2 (2H, t,J=5.7Hz), 3.25-3.45 (6H, m), 3.5-3.9 (6H, m), 5.0-5.1 (1H, m), 7.05-7.15(4H, m)

TABLE 6 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 155

1.05-1.2 (6H, m), 1.29 (3H, d, J=7.1Hz), 2.71(2H, t, J=7.0Hz), 2.85-3.0(1H, m), 3.25-3.45 (6H, m), 3.6-3.9 (4H, m), 4.19 (1H, q, J=7.1Hz),5.0-5.1 (1H, m), 7.05-7.15 (4H, m) Example 156

1.1-1.2 (6H, m), 2.71 (2H, t, J=7.0Hz), 2.85-3.0(1H, m), 3.25-3.45 (6H,m), 3.5-3.9 (9H, m), 5.0-5.1 (1H, m), 7.05-7.15 (4H, m) Example 157

1.1-1.2 (9H, m), 2.7 (2H, t, J32 7.0Hz), 2.85-3.0 (1H, m), 3.2-3.4 (6H,m), 3.55 (2H, d, J=11.0Hz), 3.59 (2H, d, J=11.0Hz), 3.6-3.9 (4H, m),5.0-5.1 (1H, m), 7.05-7.15 (4H, m) Example 158

1.1-1.2 (6H, m), 2.44 (6H, s), 2.63 (2H, t, J=6.3Hz), 2.71 (2H, t,J=6.8Hz), 2.9-3.0(1H, m), 3.25-3.4(8H, m), 3.6-3.75(2H, m), 3.75-3.85(2H, m), 5.0-5.05 (1H, m), 7.05-7.15 (4H, m) Example 159

1.1-1.2 (6H, m), 1.22 (6H, s), 2.69 (2H, t, J=7.1Hz), 2.85-3.0 (1H, m),3.2-3.4 (6H, m), 3.5 (2H, s), 3.6-3.75(2H, m), 3.75-3.9(2H, m), 5.0-5.1(1H, m), 7.05-7.15 (4H, m) Example 160

1.09(3H, d, J=6.8Hz), 1.1-1.2(6H, m), 2.7 (2H, t, J=7.0Hz), 2.85-3.0(5H, m), 5.0-5.1 (1H, m), 7.05-7.15 (4H, m)

TABLE 7 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 161

1.1-1.2 (6H, m), 2.35-2.55 (6H, m), 2.71 (2H, t, J=6.9Hz), 2.85-3.0 (1H,m), 3.23 (2H, t, J=6.2Hz), 3.25-3.4 (6H, m), 3.6-3.9 (8H, m), 5.0‥5.1(1H, m), 7.05-7.2 (4H, m) Example 162

1.05-1.2 (9H, m), 2.7 (2H, t, J=7.0Hz), 2.85-3.05 (2H, m), 3.15 (1H, dd,J=13.7Hz, 4.4Hz), 3.2-3.4 (6H, m), 3.6-3.9 (5H, m), 5.0-5.1 (1H, m),7.05-7.15 (4H, m) Example 163

0.88 (3H, d, J=6.8Hz), 0.93 (3H, d, J=6.4Hz), 1.1-1.2 (6H, m), 1.8-1.9(1H, m), 2.71 (2H, t, J=7.1Hz), 2.85-3.0 (1H, m), 3.2-3.4(6H, m),3.45-3.55(3H, m), 3.6-3.9 (4H, m), 5.0-5.1 (1H, m), 7.05-7.15 (4H, m)Example 164

1.1-1.2 (6H, m), 1.55-1.7 (1H, m), 1.8-1.9 (1H, m), 2.08 (3H, s),2.4-2.6 (2H, m), 2.65-2.8 (2H, m), 2.85-3.0 (1H, m), 3.2-3.4 (6H, m),3.44(1H, dd, J=10.9Hz, 5.4Hz), 3.5 (1H, dd, J=10.9Hz, 5.0Hz), 3.6-3.9(5H, m), 5.03 (1H, d, J=7.3Hz), 7.05-7.15 (4H, m) Example 165

1.1-1.2 (6H, m), 2.6-2.75 (3H, m), 2.8-3.0 (2H, m), 3.15-3.4 (6H, m),3.47 (1H, dd, J=10.9Hz, 5.3Hz), 3.5 (1H, dd, J=10.9Hz, 4.8Hz), 3.6-3.95(5H, m), 5.03 (1H, d, J=7.2Hz), 6.83 (1H, s), 7.0-7.15 (4H, m), 7.57(1H, d, J=1.4Hz) Example 166

1.1-1.2(6H, m), 2.65-2.75(4H, m), 2.85-3.0 (1H, m), 3.2-3.4 (8H, m),3.6-3.75 (2H, m), 3.77 (1H, d, J=16.1Hz), 3.83(1H, d, J=11.8Hz), 5.04(1H, d, J=7.2Hz), 6.81 (1H, s), 7.05-7.15 (4H, m), 7.57 (1H, d, J=1.2Hz)

TABLE 8 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 167

1.1-1.2 (9H, m), 2.73 (2H, t, J=6.9Hz), 2.85-3.0 (1H, m), 3.25-3.45 (6H,m), 3.6-3.75 (2H, m), 3.78 (1H, d, J=16.0Hz), 3.83 (1H, d, J=12.3Hz),4.05-4.15 (1H, m), 4.15-4.25 (1H, m), 5.04 (1H, d, J=7.0Hz), 7.05-7.15(4H, m) Example 168

1.1-1.2 (6H, m), 1.6-1.7 (2H, m), 2.15-2.8 (15H, m), 2.85-3.0 (1H, m),3.12 (2H, t, J=6.7Hz), 3.2-3.4 (6H, m), 3.6-3.75(2H, m), 3.78(1H, d,J=16.0Hz), 3.83 (1H, d, J=11.9Hz), 5.0-5.1 (1H, m), 7.05-7.15 (4H, m)Example 169

0.88 (3H, d, J=6.7Hz), 0.93 (3H, d, J=6.6Hz), 1.05-1.2 (6H, m), 1.8-1.9(1H, m), 2.71 (2H, t, J=6.9Hz), 2.85-3.0 (1H, m), 3.25-3.4(2H, m),3.4-3.8(10H, m), 3.8-3.9 (1H, m), 5.05 (1H, d, J=7.6Hz), 7.05-7.15 (4H,m) Example 170

0.9 (3H, d, J=7.1Hz), 0.95 (3H, d, J=6.9Hz), 1.1-1.2 (6H, m), 1.95-2.1(1H, m), 2.71 (2H, t, J=7.2Hz), 2.85-3.0 (1H, m), 3.25-3.4 (2H, m), 3.51(1H, dd, J=9.8Hz, 3.6Hz), 3.55-3.65 (1H, m), 3.65-3.8 (5H, m), 3.8-3.9(1H, m), 4.04(1H, d, J=6.1Hz), 5.05(1H, d, J=7.9Hz), 7.05-7.15 (4H, m)Example 171

1.1-1.2 (6H, m), 1.21 (6H, s), 2.69 (2H, t, J=6.9Hz), 2.78 (2H, s),2.85-3.0 (1H, m), 3.2-3.4 (6H, m), 3.6-3.9 (4H, m), 5.04 (1H, d,J=7.3Hz), 7.05-7.15 (4H, m) Example 172

1.1-1.2 (6H, m), 1.25-1.65 (6H, m) 2.6-2.75 (4H, m), 2.85-3.0(1H, m),3.2-3.55 (8H, m), 3.6-3.9 (5H, m), 5.04 (1H, d, J=7.8Hz), 7.05-7.15 (4H,m)

Reference Example 82 4-Bromo-2-methylbenzyl alcohol

To a solution of 4-bromo-2-methylbenzoic acid (10 g) in tetrahydrofuran(60 mL) was added borane-dimethylsulfide complex (7.07 g) underice-cooling. The reaction mixture was stirred at room temperature for 5minutes, and stirred at 75° C. for 2 days. The reaction mixture wascooled to room temperature. A saturated aqueous potassium carbonatesolution was added to the reaction mixture, and the organic layer wasseparated. The organic layer was washed with water and brine, and driedover anhydrous magnesium sulfate. The solvent was removed under reducedpressure to give the title compound (9.0 g).

¹H-NMR (CDCl₃) δ ppm: 1.55-1.65 (1H, m), 2.36 (3H, s), 4.64 (2H, d,J=5.4 Hz), 7.2-7.25 (1H, m), 7.3-7.35 (2H, m)

Reference Example 834-{[4-(2-Aminoethyl)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) indichloromethane (50 mL) was added thionyl chloride (3.8 mL) underice-cooling, and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureto give 4-bromo-2-methylbenzyl chloride (9.8 g). Sodium hydride (55%,0.84 g) was suspended in tetrahydrofuran (80 mL). To the suspension wasadded methyl 4-methyl-3-oxopentanoate (2.94 g) under ice-cooling, andthe mixture was stirred at room temperature for 1 hour. To the reactionmixture was added 4-bromo-2-methylbenzyl chloride (4.08 g), and themixture was stirred at 60 C.° for 36 hours. To the reaction mixture wasadded a saturated aqueous ammonium chloride solution, and the resultingmixture was extracted with diethyl ether. The extract was dried overanhydrous magnesium sulfate, and the solvent was removed under reducedpressure. The residue was dissolved in acetonitrile (24 mL). To thesolution were added N-vinylphthalimide (3.29 g), palladium acetate(II)(0.42 g), tris(o-methylphenyl)phosphine (2.27 g) andN,N-diisopropylethylamine (13 mL), and the mixture was stirred at 100C.° for 16 hours. The reaction mixture was concentrated under reducedpressure, and the residue was purified by column chromatography onsilica gel (eluent: n-hexane-n-hexane/ethyl acetate=3/1-3/2) to giveN-{(E)-2-[4-(2-methoxycarbonyl-4-methyl-3-oxopentyl)-3-methylphenyl]-vinyl}phthalimide(6.45 g). To this material were added methanol (50 mL) and 10%palladium-carbon powder (3 g), and the mixture was stirred at roomtemperature under a hydrogen atmosphere for 2 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure. A part (1 g) of the residue was dissolved inethanol (15 mL). To the solution was added hydrazine monohydrate (1.38mL), and the mixture was stirred at 80 C.° for 13 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by solid phaseextraction on ODS (washing solvent: distilled water, eluent: methanol)and benzenesulfonic acid resin (washing solvent: methanol, eluent: 2mol/L ammonia-methanol solution) to give the title compound (0.3 g).

¹H-NMR (DMSO-d₆) δ ppm: 1.04 (6H, d, J=6.7 Hz), 2.25 (3H, s), 2.53 (2H,t, J=7.2 Hz), 2.65-2.8 (3H, m), 3.47 (2H, s), 6.75-6.9 (2H, m), 6.93(1H, s)

Reference Example 844-({4-[2-(Benzyloxycarbonylamino)ethyl]-2-methylphenyl}-methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

To a solution of4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one(0.3 g) in tetrahydrofuran (5 mL) was addedN-(benzyloxycarbonyloxy)succinimide (0.33 g), and the mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto water, and the resulting mixture was extracted with ethyl acetate.The extract was washed with a saturated aqueous sodium hydrogencarbonate solution twice, water and brine, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive the title compound (0.34 g).

¹H-NMR (CDCl₃) δ ppm: 1.11 (6H, d, J=6.7 Hz), 2.31 (3H, s), 2.65-2.95(3H, m), 3.35-3.5 (2H, m), 3.63 (2H, s), 4.65-4.8 (1H, m), 5.09 (2H, s),6.85-7.0 (3H, m), 7.25-7.4 (5H, m)

Example 1733-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}methyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneinstead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.79 (3H, s), 1.98 (3H, s),2.02 (3H, s), 2.05 (3H, s), 2.26 (3H, s), 2.73 (2H, t, J=6.7 Hz),2.75-2.9 (1H, m), 3.35-3.45 (2H, m), 3.53 (1H, d, J=16.5 Hz), 3.62 (1H,d, J=16.5 Hz), 3.75-3.85 (1H, m), 4.08 (1H, dd, J=12.5 Hz, 2.7 Hz), 4.27(1H, dd, J=12.5 Hz, 4.1 Hz), 4.8-4.9 (1H, m), 5.09 (2H, s), 5.1-5.3 (3H,m), 5.55 (1H, d, J=7.7 Hz), 6.8-6.9 (2H, m), 6.93 (1H, s), 7.25-7.4 (5H,m)

Example 1744-{[4-(2-Aminoethyl)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole(20 mg) was dissolved in methanol (1 mL). To the solution was addedsodium methoxide (28% methanol solution, 0.005 mL), and the mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl)methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole.This material was dissolved in methanol (1 mL). To the solution wasadded 10% palladium-carbon powder (5 mg), and the mixture was stirred atroom temperature under a hydrogen atmosphere for 6 hours. The insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (11 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 2.31 (3H, s), 2.67 (2H, t,J=7.0 Hz), 2.75-2.9 (3H, m), 3.25-3.4 (4H, m), 3.6-3.85 (4H, m),4.95-5.05 (1H, m), 6.85-7.0 (3H, m)

Example 1754-{[4-(2-[(3-[(1S,2R)-1-Carbamoyl-2-hydroxypropyl]ureido}-ethyl)-2-methylphenyl]methyl}-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole(0.3 g) was dissolved in tetrahydrofuran (2 mL). To the solution wasadded 10% palladium-carbon powder (20 mg), and the mixture was stirredat room temperature under a hydrogen atmosphere for 6 hours. Theinsoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(0.24 g). The obtained3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethyl)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole(0.13 g) was dissolved in dichloromethane (2.6 mL). To the solution wereadded triethylamine (0.042 mL) and 4-nitrophenyl chloroformate (52 mg)under ice-cooling, and the mixture was stirred at room temperature for 2hours. A ¼ amount of the reaction mixture was separated. To the part ofthe reaction mixture were added triethylamine (0.028 mL) and L-threonineamide hydrochloride (23 mg), and the mixture was stirred at roomtemperature overnight. The reaction mixture was purified by columnchromatography on silica gel (eluent: ethyl acetate-ethylacetate/methanol=10/1) to give3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-(3-[(1S,2R)-1-carbamoyl-2-hydroxypropyl]-ureido}ethyl)-2-methylphenyl]methyl)-5-isopropyl-1H-pyrazole(30 mg). This material was dissolved in methanol (2 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.006 mL), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added acetic acid (0.005 mL). The resulting mixture wasconcentrated under reduced pressure, and the residue was purified bysolid phase extraction on ODS (washing solvent: distilled water, eluent:methanol) to give the title compound (21 mg).

¹H-NMR (CD₃OD) δ ppm: 1.1-1.2 (9H, m), 2.31 (3H, s), 2.7 (2H, t, J=7.0Hz), 2.8-2.9 (1H, m), 3.2-3.45 (6H, m), 3.6-3.75 (3H, m), 3.8 (1H, dd,J=12.1 Hz, 2.1 Hz), 4.05-4.15 (1H, m), 4.15-4.25 (1H, m), 4.97 (1H, d,J=7.0 Hz), 6.85-6.95 (2H, m), 7.0 (1H, s)

Examples 176-181

The compounds described in Tables 9-10 were prepared in a similar mannerto that described in Example 175 using the corresponding startingmaterials. The syntheses of Examples 180 and 181 were carried out bycatalytic hydrogenation in a similar manner to that described in Example79 after the completion of the operation of Example 175. TABLE 9 ExampleNo. Structure ¹H-NMR (CD₃OD) δ ppm: Example 176

1.1-1.2(6H, m), 2.31 (3H, s), 2.69 (2H, t, J=7.0Hz), 2.75-2.9(1H, m),3.2-3.4 (6H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.97 (1H, d,J=6.9Hz), 6.85-6.95 (2H, m), 6.99 (1H, s) Example 177

1.05-1.2 (9H, m), 2.31 (3H, s), 2.6-2.75 (2H, m), 2.75-2.9 (1H, m),3.2-3.4 (6H, m), 3.5-3.75 (7H, m), 3.8 (1H, d, J=11.6Hz), 4.9-5.05 (1H,m), 6.85-6.95 (2H, m), 6.99 (1H, s)

TABLE 10 Example No. Structure ¹H-NMR (CD₃OD) δ ppm: Example 178

1.1-1.2 (6H, m), 2.25 (6H, s), 2.31 (3H, s), 2.4(2H, t, J=6.5Hz), 2.68(2H, t, J=6.7Hz), 2.8-2.9 (1H, m), 3.15-3.4 (8H, m), 3.6-3.75 (3H, m),3.75-3.85 (1H, m), 4.9-5.0 (1H, m), 6.85-6.95 (2H, m), 6.98 (1H, s)Example 179

0.91 (3H, d, J=6.7Hz), 0.96 (3H, d, J=6.6Hz), 1.05-1.2 (6H, m), 1.95-2.1(1H, m), 2.3 (3H, s), 2.65-2.75(2H, m), 2.8-2.9(1H, m), 3.2-3.45 (6H,m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m), 4.05 (1H, d, J=6.1Hz), 4.9-5.05(1H, m), 6.85-6.95 (2H, m), 6.99 (1H, s) Example 180

1.1-1.2 (6H, m), 1.3-1.85 (6H, m), 2.31 (3H, s), 2.6-2.75 (4H, m),2.8-2.9 (1H, m), 3.2-3.45 (6H, m), 3.6-3.75 (3H, m), 3.75-3.85 (1H, m),4.05-4.2 (1H, m), 4.9-5.0 (1H, 3.6-3.75 (3H, m), 3.75-3.85 (1H, m),6.85-7.0 (3H, m) Example 181

1.05-1.2 (6H, m), 1.3-1.65 (6H, m), 2.31 (3H, s), 2.6-2.75 (4H, m),2.8-2.9 (1H, m), 3.2-3.55 (8H, m), 3.55-3.75 (4H, m), 3.75-3.85 (1H, m),4.98(1H, d, J=7.5Hz), 6.85-7.0 (3H, m)

Example 1823-(β-D-Galactopyranosyloxy)-5-isopropyl-4-[(4-{3-[3-(dimethylamino)propylamino]propoxy}-2-methylphenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 51 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand N,N-dimethyl-N′-(2-nitrobenzenesulfonyl)-1,3-diaminopropane insteadof3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 2-methyl-2-(2-nitrobenzenesulfonylamino)-propionamide, respectively.

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.65-1.75 (2H, m), 1.9-2.0 (2H,m), 2.23 (6H, s), 2.28 (3H, s), 2.3-2.4 (2H, m), 2.61 (2H, t, J=7.3 Hz),2.7-2.85 (3H, m), 3.49 (1H, dd, J=9.8 Hz, 3.5 Hz), 3.55-3.8 (6H, m),3.84 (1H, d, J=3.5 Hz), 3.99 (2H, t, J=6.1 Hz), 5.03 (1H, d, J=7.9 Hz),6.6 (1H, d, J=8.7 Hz, 2.4 Hz), 6.7 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.7Hz)

Reference Example 85 3-Amino-3-methylbutyramide

To a solution of 3,3-dimethylacrylic acid (5 g) in tetrahydrofuran (15mL) was added 1,1′-carbonylbis-1H-imidazole (10.5 g), and the mixturewas stirred at room temperature for 30 minutes. To the reaction mixturewas added 28% aqueous ammonia solution (30 mL), and the mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give 3,3-dimethylacrylamide (2.05 g).This material was dissolved in 2-propanol (20 mL). An ammonia gas wasbubbled into the solution at −15 C.° until saturation, and the mixturewas stirred at 80 C.° for 40 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bybenzenesulfonic acid resin (washing solvent: methanol, eluent: 2 mol/Lammonia-methanol solution) to give the title compound (0.13 g).

¹H-NMR (CD₃OD) δ ppm: 1.19 (6H, s), 2.27 (2H, s)

Example 1834-[(4-{3-[2-Carbamoyl-1,1-di(methyl)ethylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 72 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazoleand 3-amino-3-methylbutyramide instead of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazoleand 2-[2-amino-2-(methyl)-propionylamino]ethanol, respectively.

MS(ESI, m/z): 565 [M+H]⁺

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.18 (6H, s), 1.85-2.0 (2H, m),2.28 (3H, s), 2.32 (2H, s), 2.7-2.85 (3H, m), 3.49 (1H, dd, J=9.7 Hz,3.3 Hz), 3.58 (1H, t, J=5.8 Hz), 3.6-3.8 (5H, m), 3.8-3.9 (1H, m), 4.0(2H, t, J=5.9 Hz), 5.03 (1H, d, J=7.9 Hz), 6.55-6.65 (1H, m), 6.65-6.75(1H, m), 6.8-6.9 (1H, m)

Reference Example 864-[(4-Benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inReference Example 11 using (4-benzyloxy-2-methylphenyl)methanol andethyl trifluoroacetoacetate instead of(4-(3-benzyloxypropoxy)phenyl]methanol and ethyl4-methyl-3-oxopentanoate, respectively.

¹H-NMR (DMSO-d₆) δ ppm: 2.24 (3H, s), 3.58 (2H, s), 5.02 (2H, s), 6.65(1H, d, J=8.5 Hz), 6.7 (1H, dd, J=8.5 Hz, 2.7 Hz), 6.81 (1H, d, J=2.7Hz), 7.25-7.45 (5H, m)

Reference Example 873-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

A suspension of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one(0.5 g), acetobromo-α-D-galactose (0.62 g) and potassium carbonate (0.29g) in acetonitrile (5 mL) was stirred at room temperature overnight. Thereaction mixture was poured into water, and the resulting mixture wasextracted with ethylacetate. The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyon silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the titlecompound (0.66 g).

¹H-NMR (CDCl₃) δ ppm: 1.78 (3H, s), 1.98 (3H, s), 2.05 (3H, s), 2.17(3H, s), 2.3 (3H, s), 3.67 (1H, d, J=16.4 Hz), 3.72 (1H, d, J=16.4 Hz),3.98 (1H, t, J=6.3 Hz), 4.1-4.25 (2H, m), 5.0-5.1 (3H, m), 5.15-5.4 (2H,m), 5.42 (1H, dd, J=3.4 Hz, 1.0 Hz), 6.67 (1H, dd, J=8.5 Hz, 2.6 Hz),6.75 (1H, d, J=8.5 Hz), 6.8 (1H, d, J=2.6 Hz), 7.25-7.45 (5H, m)

Reference Example 883-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-5-trifluoromethyl-4-[(4-hydroxy-2-methylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 58 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole.

H-NMR (CDCl₃) δ ppm: 1.83 (3H, s), 1.98 (3H, s), 2.05 (3H, s), 2.18 (3H,s), 2.27 (3H, s), 3.66 (1H, d, J=16.4 Hz), 3.71 (1H, d, J=16.4 Hz),3.95-4.0 (1H, m), 4.05-4.2 (2H, m), 4.84 (1H, brs), 5.03 (1H, dd, J=10.3Hz, 3.4 Hz), 5.2-5.4 (2H, m), 5.41 (1H, dd, J=3.4 Hz, 1.1 Hz), 6.54 (1H,dd, J=8.3 Hz, 2.7 Hz), 6.64 (1H, d, J=2.7 Hz), 6.72 (1H, d, J=8.3 Hz)

Example 1844-[(4-{3-[(2-(Carbamoyl)ethylamino]propoxy}-2-methylphenyl)-methyl]-5-trifluoromethyl-3-(β-D-galactopyranosyloxy)-1H-pyrazole

3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[N-benzyloxycarbonyl-N-(2-carbamoylethyl)amino]-propoxy}-2-methylphenyl)methyl]-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Example 96 using3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-5-trifluoromethyl-4-[(4-hydroxy-2-methylphenyl)methyl]-1H-pyrazoleinstead of4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole,and the title compound was prepared in a similar manner to thatdescribed in Example 94 using this material instead of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole.

MS(ESI, m/z): 563 [M+H]⁺

¹H-NMR (CD₃OD) δ ppm: 1.95-2.1 (2H, m), 2.25 (3H, s), 2.41 (2H, t, J=6.9Hz), 2.63 (2H, t, J=7.1 Hz), 2.83 (2H, t, J=6.9 Hz), 3.53 (1H, dd, J=9.8Hz, 3.4 Hz), 3.55-3.8 (6H, m), 3.87 (1H, d, J=3.4 Hz), 4.21 (2H, t,J=6.7 Hz), 5.28 (1H, d, J=7.9 Hz), 6.45 (1H, dd, J=8.4 Hz, 2.4 Hz),6.55-6.65 (2H, m)

Example 1854-[(4-{2-[2-{[4-(Benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)-methyl]3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole(0.5 g) in N,N-dimethylformamide (10 mL) were added1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)-propionyl]piperazine (0.28g), 1-hydroxybenzotriazole (0.22 g), triethylamine (0.18 mL) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.46 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was poured into water, and the resulting mixture was extractedwith diethyl ether. The organic layer was washed with a saturatedaqueous sodium hydrogen carbonate solution, water and brinesuccessively, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=30/1) togive3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)-methyl]-5-isopropyl-1H-pyrazole(0.3 g). This material was dissolved in methanol (4 mL). To the solutionwas added sodium methoxide (28% methanol solution, 0.06 mL), and themixture was stirred at room temperature for 30 minutes. To the reactionmixture was added acetic acid (0.035 mL), and the resulting mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1)to give the title compound (0.23 g).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.15 (6H, m), 1.37 (6H, s), 2.25 (3H, s),2.7-2.85 (1H, m), 3.15-3.75 (17H, m), 3.81 (1H, d, J=12.0 Hz), 4.02 (2H,t, J=5.2 Hz), 5.02 (1H, d, J=7.4 Hz), 5.09 (2H, s), 6.55-6.65 (1H, m),6.69 (1H, d, J=2.2 Hz), 6.84 (1H, d, J=8.7 Hz), 7.25-7.4 (5H, m)

Reference Example 894-[(4-{2-[2-{[4-(Benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)-methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one

A mixture of4-[(4-{2-[2-{[4-(benzyloxycarbonyl)-piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole(0.23 g), p-toluenesulfonic acid monohydrate (0.41 g) and 2-propanol (10mL) was stirred at 50 C.° for 2 days. The reaction mixture was pouredinto a saturated aqueous sodium hydrogen carbonate solution, and theresulting mixture was extracted with ethyl acetate. The extract waswashed with water and brine, and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give the title compound (0.18 g).

¹H-NMR (CD₃OD) δ ppm: 1.06 (6H, d, J=6.7 Hz), 1.37 (6H, s), 2.25 (3H,s), 2.7-2.85 (1H, m), 3.15-3.7 (12H, m), 4.02 (2H, t, J=5.3 Hz), 5.09(2H, s), 6.6 (1H, dd, J=8.6 Hz, 2.3 Hz), 6.7 (1H, d, J=2.3 Hz), 6.85(1H, d, J=8.6 Hz), 7.25-7.4 (5H, m)

Example 1863-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inReference Example 17 using4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)-propionylamino]ethoxy}-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-galactose instead of4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-oneand acetobromo-α-D-glucose, respectively.

¹H-NMR (CDCl₃) δ ppm: 1.05-1.15 (6H, m), 1.41 (6H, s), 1.83 (3H, s),1.98 (3H, s), 2.02 (3H, s), 2.15 (3H, s), 2.25 (3H, s), 2.7-2.85 (1H,m), 3.25-3.7 (12H, m), 3.97 (2H, t, J=4.9 Hz), 4.0-4.1 (1H, m), 4.1-4.2(2H, m), 5.08 (1H, dd, J=10.4 Hz, 3.5 Hz), 5.12 (2H, s), 5.35-5.45 (2H,m), 5.52 (1H, d, J=8.1 Hz), 5.92 (1H, t, J=5.7 Hz), 6.53 (1H, dd, J=8.4Hz, 2.6 Hz), 6.63 (1H, d, J=2.6 Hz), 6.81 (1H, d, J=8.4 Hz), 7.25-7.4(5H, m)

Example 1873-(β-D-Galactopyranosyloxy)-5-isopropyl-4-{[4-(2-{2-methyl-2-[(piperazin-1-yl)carbonyl]propionylamino}ethoxy)-2-methylphenyl]methyl}-1H-pyrazole

To a solution of3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole(0.14 g) in methanol (3 mL) was added sodium methoxide (28% methanolsolution, 0.015 mL), and the mixture was stirred at room temperature for30 minutes. The reaction mixture was purified by column chromatographyon silica gel (eluent: dichloromethane/methanol=5/1) to give4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)-methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole(70 mg). This material was dissolved in methanol (4 mL). To the solutionwas added 10% palladium-carbon powder (10 mg), and the mixture wasstirred at room temperature under a hydrogen atmosphere for 1 hour. Theinsoluble material was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give the title compound (54 mg).

¹H-NMR (CD₃OD) δ ppm: 1.05-1.2 (6H, m), 1.37 (6H, s), 2.3 (3H, s),2.35-2.9 (5H, m), 3.1-3.8 (13H, m), 3.85 (1H, d, J=3.3 Hz), 4.02 (2H, t,J=5.5 Hz), 5.04 (1H, d, J=8.0 Hz), 6.62 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.72(1H, d, J=2.4 Hz), 6.86 (1H, d, J=8.4 Hz)

Test Example 1

Assay for Inhibitory Effects on Human SGLT1 Activity

1) Cloning and Construction of the Vector Expressing Human SGLT1

The cDNA library was prepared for PCR amplification by reversetranscription from total RNA deprived from human small intestine (Origene) using oligo-dT as a primer. Using this cDNA library as a template,the DNA fragment coding 1 to 2005 bp of human SGLT1 (ACCESSION: M24847),which was reported by Hediger et al., was amplified by PCR method andinserted into the multi-cloning site of pcDNA3.1(−) (Invitrogen). TheDNA sequence inserted was perfectly matched to the previously reportedsequence.

2) Establishment of Cell Line Stably Expressing Human SGLT1

The expression vector of human SGLT1 was digested by Sca I into a linearDNA. The linear DNA was transfected into CHO-K1 cells by means oflipofection (Effectene Transfection Reagent: QIAGEN). Neomycin resistantcell lines were selected by culture in the medium containing G418 (1mg/mL, LIFE TECHNOLOGIES), and then the activity against the uptake ofmethyl-α-D-glucopyranoside was measured by the method described below.The cell line, which showed the greatest uptake activity, was selectedand designated as CS1-5-11D. CS1-5-11D cells were cultured in thepresence of G418 at 200 μg/mL.

3) Measurement of the Inhibitory Activity Against the Uptake ofmethyl-α-D-glucopyranoside (α-MG)

CS1-5-11D cells were seeded into a 96-well culture plate at a density of3×10⁴ cells/well and cultured for 2 days, and were used in the uptakeassay. A mixture of non-labeled (Sigma) and ¹⁴C-labeled α-MG (AmershamPharmcia Biotec) was added to the uptake buffer (pH 7.4; containing 140mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, and 5 mM tris (hydroxymethyl) aminomethane) at the finalconcentration of 1 mM. A test compound was dissolved in dimethylsulfoxide, and then appropriately diluted with distilled water. The testcompound solution was added to the uptake buffer containing 1 mM α-MG,and designated as a measurement buffer. For the control group, themeasurement buffer without any test compound was prepared. For measuringthe basal uptake, a basal uptake measurement buffer which contains 140mM chorine chloride instead of sodium chloride was prepared. Afterremoving the culture medium of CS1-5-11D cells, 180 μL of thepre-treatment buffer (the basal uptake buffer without α-MG) was added toeach well and incubated at 37° C. for 10 minutes. After repeating thesame treatment, the pre-treatment buffer was removed. To each well wasadded 75 μL of the measurement buffer or the basal uptake buffer wasadded and incubated at 37° C. for 1 hour. After removing the measurementbuffer, cells were washed twice with 180 μL per well of the washingbuffer (the basal uptake buffer containing 10 mM non-labeled α-MG). Thecells were solubilized by 75 μL per well of 0.2 mol/L sodium hydroxide.The cell lysates were transferred into PicoPlates (Packard), and thenadded 150 μL of MicroScint-40 (Packard) and mixed. Radioactivity wasmeasured by means of micro-scintillation counter TopCount (Packard). Onehundred % was set to the difference between the uptake in the controlgroup and the basal uptake, and the uptake of methyl α-D-glucopyranosideat each drug concentration were calculated. The drug concentration, atwhich 50% uptake of methyl α-D-glucopyranoside was inhibited (IC₅₀value), was calculated using logit plot. The results are shown in Table11. TABLE 11 Test compound IC₅₀ value (nM) Example 6 304 Example 9 42Example 10 169 Example 13 267 Example 21 127 Example 22 233 Example 2461 Example 28 90 Example 29 19 Example 30 257 Example 31 166 Example 32113 Example 33 65 Example 35 160 Example 36 383 Example 37 158 Example38 246 Example 45 68 Example 48 54 Example 49 148 Example 50 159 Example51 22 Example 52 131 Example 55 98 Example 56 38 Example 57 43 Example58 100 Example 59 71 Example 61 199 Example 62 138 Example 63 322Example 64 178

Test Example 2

Assay for Inhibitory Effects on Blood Glucose Level Increase in Rats

1) Preparation of Diabetic Rat Model

Male wistar rats (Japan Charles River), aged 8 weeks old, were injectednicotinamide (230 mg/kg) intraperitoneally. Fifteen minutes afterinjection, they were injected streptozotocin (85 mg/kg) intravenouslyfrom tail vain under anesthesia with ether. After a week, rats werefasted overnight and then glucose tolerance test (2 g/kg) was done. Therats which showed plasma glucose concentration at 1 hour after glucoseload was over 300 mg/dL were selected to use liquid meal tolerance test.

2) Liquid Meal Tolerance Test

After overnight fasted, the diabetic rats were orally administered atest compound (1 mg/kg), which was dissolved in distilled water or 0.5%aqueous carboxymethylcellulose solution, in the drug-treating group, ordistilled water or 0.5% aqueous carboxymethylcellulose solution alone ina control group. Immediately after the compound administration, 17.25kcal/kg of liquid meal (No. 038, Control diet, assorted with dextrin andmaltose; Oriental Yeast Co., Ltd.) was loaded orally. The blood wascollected from tail artery immediately before and after administrationwith the time course, and treated with heparin immediately. The bloodwas centrifuged, and the plasma was collected to quantify the plasmaglucose concentration by glucose oxidase method. Plasma glucoseconcentrations at pretreatment (0 h), 0.5 and 1 hour after the drugadministration are shown in Table 12. The values in the Table arepresented as the mean±S.E. TABLE 12 Plasma glucose Test concentration(mg/dL) compound 0 h 0.5 h 1 h Control  95 ± 5 219 ± 12 246 ± 17 Example6  97 ± 10 126 ± 12 140 ± 13 Control 122 ± 6 258 ± 32 260 ± 35 Example10 120 ± 10 145 ± 5 164 ± 6 Control 106 ± 4 199 ± 8 196 ± 15 Example 13108 ± 8 127 ± 7 135 ± 7 Control 115 ± 3 276 ± 25 261 ± 32 Example 21 122± 11 211 ± 22 242 ± 35 Example 35 113 ± 4 188 ± 16 229 ± 25 Control 140± 13 313 ± 48 283 ± 52 Example 24 146 ± 7 210 ± 33 228 ± 50 Control 131± 7 330 ± 37 306 ± 45 Example 37 132 ± 5 231 ± 21 286 ± 31 Control 123 ±10 305 ± 18 304 ± 23 Example 45 129 ± 11 169 ± 18 182 ± 27 Control 124 ±5 278 ± 31 274 ± 22 Example 52 138 ± 4 163 ± 5 176 ± 10 Control 123 ± 8292 ± 28 294 ± 29 Example 55 122 ± 5 200 ± 16 211 ± 18 Example 59 115 ±7 143 ± 4 154 ± 13 Control 121 ± 7 313 ± 33 303 ± 63 Example 56 109 ± 10146 ± 7 165 ± 17 Control  91 ± 12 238 ± 4 213 ± 22 Example 64 116 ± 2141 ± 12 148 ± 22

Test Example 3

Acute Toxicity Test

Male ICR mice (CLEA Japan, Inc.; 32-37 g, n=5), aged 6 weeks old, werefasted for 4 hours. A test compound, which was dissolved in distilledwater, was administered orally at a dose of 1 g/kg, and then mice wereobserved for 24 hours. The results are shown in the following Table 13.TABLE 13 Test compound Number of death Example 52 0/5

INDUSTRIAL APPLICABILITY

The pyrazole derivatives represented by the above general formula (I) ofthe present invention, pharmaceutically acceptable salts thereof andprodrugs thereof exert an inhibitory activity in human SGLT1 and cansuppress increase of blood glucose level by inhibiting absorption ofcarbohydrate such as glucose at the small intestine, and particularly,can suppress remarkably increase of blood glucose level and/or can lowerblood galactose level by delaying absorption of glucose and galactosebased on the mechanism, and for example, can normalize postprandialhyperglycemia. Therefore, the present invention can provide excellentagents for the prevention or treatment of a disease associated withhyperglycemia such as diabetes, impaired glucose tolerance, impairedfasting glycemia, diabetic complications, obesity or the like, and adisease associated with the increase of blood galactose level such asgalactosemia. In addition, since the pyrazole derivatives represented bythe above general formula (II) of the present invention and saltsthereof are important as intermediates in the production of the pyrazolederivatives represented by the above general formula (I), the compoundsrepresented by the above general formula (I) of the present inventioncan be readily prepared via such compounds.

1. A pyrazole derivative represented by the general formula:

wherein R¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group, a C₃₋₇ cycloalkyl group, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or an aryl(C₁₋₆ alkyl) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring; one of Q and T represents a group represented by the formula:

or a group represented by the formula:

while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group; R² represents a hydrogen atom, a halogen atom, a hydroxy group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆ alkyl) group, a halo(C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group or -A-R^(A) in which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—; and R^(A) represents a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a C₁₋₆ alkyl group; X represents a single bond, an oxygen atom or a sulfur atom; Y represents a C₁₋₆ alkylene group which may be substituted by a hydroxy group or a C₂₋₆ alkenylene group; Z represents —R^(B), —COR^(C), —SO₂R^(C), —CON(R^(D))R^(E), —SO₂NHR^(F) or —C(═NR^(G))N(R^(H))R^(I); R^(C) represents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i); R⁴, R^(B), R^(D), R^(E) and R^(F) are the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R⁴ and R^(B) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, or both of R^(D) and R^(E) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group; R^(G), R^(H) and R^(I) are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C₂₋₇ acyl group, a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group, a nitro group, a C₁₋₆ alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R^(G) and R^(H) bind to form an ethylene group, or both of R^(H) and R^(I) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group; R³, R⁵ and R⁶ are the same or different, and each represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group; and substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or different, and each represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or both of R^(J) and R^(K) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆ alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl group as a substituent, or a pharmaceutically acceptable salt thereof.
 2. A pyrazole derivative claimed in claim 1, wherein R⁴ represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i); R^(B) represents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i); R^(C) represents an aryl group which has the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which has the same or different 1 to 5 groups selected from the following substituent group (i); and substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or different, and each represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or both of R^(J) and R^(K) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆ alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl group as a substituent, or a pharmaceutically acceptable salt thereof.
 3. A pyrazole derivative claimed in claim 2, wherein Z represents —R^(B); R^(B) represents an aryl group which has the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which has the same or different 1 to 5 groups selected from the following substituent group (i); and substituent group (i) consists of a hydroxy group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkylsulfonyl group, a carboxy group, a C₂₋₇ alkoxycarbonyl group, —CON(R^(J))R^(K) in which R^(J) and R^(K) are the same or different, and each represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group, an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or both of R^(J) and R^(K) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆ alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl group as a substituent, or a pharmaceutically acceptable salt thereof.
 4. A pyrazole derivative claimed in claim 3, wherein R⁴ represents a hydrogen atom; R^(B) represents a C₁₋₆ alkyl group which has the same or different 1 to 5 groups selected from the following substituent group (iA); and substituent group (iA) consists of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, a carboxy group, a C₂₋₇ alkoxycarbonyl group and —CON(R^(JA))R^(KA) in which R^(JA) and R^(KA) are the same or different, and each represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group and a carbamoyl group, or both of R^(JA) and R^(KA) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, or a pharmaceutically acceptable salt thereof.
 5. A pyrazole derivative claimed in claim 4, wherein R^(B) represents a C₁₋₆ alkyl group which has a carbamoyl group, or a pharmaceutically acceptable salt thereof.
 6. A pyrazole derivative claimed in claim 2, wherein Z represents —CON(R^(D))R^(E), or a pharmaceutically acceptable salt thereof.
 7. A pyrazole derivative claimed in claim 6, wherein R^(D) represents a hydrogen atom; R^(E) represents a C₁₋₆ alkyl group which has the same or different 1 to 5 groups selected from the following substituent group (iB); and substituent group (iB) consists of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group and —CON(R^(JB))R^(KB) in which R^(JB) and R^(KB) are the same or different, and each represents a hydrogen atom, a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group and a mono or di(C₁₋₆ alkyl)amino group, or pharmaceutically acceptable salt thereof.
 8. A pyrazole derivative claimed in claim 2, wherein Z represents —C(═NR^(G))N(R^(H))R^(I), or pharmaceutically acceptable salt thereof.
 9. A pyrazole derivative claimed in claim 8, wherein R^(G) represents a hydrogen atom or a C₁₋₆ alkylsulfonyl group; R^(H) represents a hydrogen atom; R^(I) represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (iC); and substituent group (iC) consists of a hydroxy group, an amino group, a mono or di(C₁₋₆ alkyl)amino group, or pharmaceutically acceptable salt thereof.
 10. A pyrazole derivative claimed in claim 2, wherein Z represents —COR^(C); R^(C) represents a C₁₋₆ alkyl group which has a group selected from the following substituent group (iD); and substituent group (iD) consists of an amino group and —CON(R^(JC))R^(KC) in which both of R^(JC) and R^(KC) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a C₁₋₆ alkyl group and a hydroxy(C₁₋₆ alkyl) group, or pharmaceutically acceptable salt thereof.
 11. A pyrazole derivative claimed in claim 1, wherein X represents a single bond or an oxygen atom; and Y represents an ethylene group or a trimethylene group, or pharmaceutically acceptable salt thereof.
 12. A pyrazole derivative claimed in claim 1, wherein R¹ represents a hydrogen atom or a hydroxy(C₂₋₆ alkyl) group; T represents a group represented by the formula:

or a group represented by the formula:

Q represents a C₁₋₆ alkyl group or a halo(C₁₋₆ alkyl) group; and R³, R⁵ and R⁶ represent a hydrogen atom, or a pharmaceutically acceptable salt thereof.
 13. A pyrazole derivative claimed in claim 1 wherein one of Q and T represents a group represented by the formula:

the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group, or a pharmaceutically acceptable salt thereof.
 14. A pyrazole derivative claimed in claim 12, wherein T represents a group represented by the formula:

or a pharmaceutically acceptable salt thereof.
 15. A pyrazole derivative claimed in claim 12, wherein Q represents an isopropyl group, or a pharmaceutically acceptable salt thereof.
 16. A prodrug of a pyrazole derivative claimed in claim 1 or a pharmaceutically acceptable salt thereof.
 17. A prodrug claimed in claim 16, wherein T represents a group represented by the formula:

or a group represented by the formula:

in which the hydroxy group at the 4-position is substituted by a glucopyranosyl group or a galactopyranosyl group, or the hydroxy group at the 6-position is substituted by a glucopyranosyl group, a galactopyranosyl group, a C₂₋₇ acyl group, a C₁₋₆ alkoxy-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl-substituted (C₂₋₇ acyl) group, a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group or a C₁₋₆ alkoxy-substituted (C₂₋₇ alkoxycarbonyl) group.
 18. A pyrazole derivative as claimed in claim 1, which is a compound selected from the following group and pharmaceutically acceptable salts thereof


19. A pharmaceutical composition comprising as an active ingredient a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 20. A human SGLT1 inhibitor comprising as an active ingredient a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 21. An agent for inhibiting postprandial hyperglycemia comprising as an active ingredient a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 22. An agent for the prevention or treatment of a disease associated with hyperglycemia, which comprises as an active ingredient a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 23. An agent for the prevention or treatment claimed in claim 22, wherein the disease associated with hyperglycemia is a disease selected from the group consisting of diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout.
 24. An agent for the inhibition of advancing impaired glucose tolerance or impaired fasting glycemia into diabetes in a subject, which comprises as an active ingredient a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 25. An agent for the prevention or treatment of a disease associated with the increase of blood galactose level, which comprises as an active ingredient a pyrazole derivative claimed claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 26. An agent for the prevention or treatment claimed in claim 25, wherein the disease associated with the increase of blood galactose level is galactosemia.
 27. A pharmaceutical composition claimed in claim 19, wherein the dosage form is sustained release formulation.
 28. An agent claimed in claim 20, wherein the dosage form is sustained release formulation.
 29. A method for the prevention or treatment of a disease associated with hyperglycemia, which comprises administering an effective amount of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 30. A method for the inhibition of advancing impaired glucose tolerance or impaired fasting glycemia into diabetes in a subject, which comprises administering an effective amount of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 31. A method for the prevention or treatment of a disease associated with the increase of blood galactose level, which comprises administering an effective amount of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof.
 32. A use of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease associated with hyperglycemia.
 33. A use of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a pharmaceutical composition for the inhibition of advancing impaired glucose tolerance or impaired fasting glycemia into diabetes in a subject.
 34. A use of a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease associated with the increase of blood galactose level.
 35. A pharmaceutical combination which comprises (A) a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcript factor NF-κB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth factor analogue, epidermal growth factor, nerve growth factor, a carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihypertensive agent, a sympathetic blocking agent, a centrally acting antihypertensive agent, an α₂-adrenoceptor agonist, an antiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agent and a urinary alkalinizer.
 36. A method for the prevention or treatment of a disease associated with hyperglycemia or a disease associated with the increase of blood galactose level, which comprises administering an effective amount of (A) a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcript factor NF-κB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth factor analogue, epidermal growth factor, nerve growth factor, a carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihypertensive agent, a sympathetic blocking agent, a centrally acting antihypertensive agent, an α₂-adrenoceptor agonist, an antiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agent and a urinary alkalinizer.
 37. A method for the inhibition of advancing impaired glucose tolerance or impaired fasting glycemia into diabetes in a subject, which comprises administering an effective amount of (A) a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcript factor NF-κB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth factor analogue, epidermal growth factor, nerve growth factor, a carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihypertensive agent, a sympathetic blocking agent, a centrally acting antihypertensive agent, an α₂-adrenoceptor agonist, an antiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agent and a urinary alkalinizer.
 38. A use of (A) a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcript factor NF-κB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth factor analogue, epidermal growth factor, nerve growth factor, a carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihypertensive agent, a sympathetic blocking agent, a centrally acting antihypertensive agent, an α2-adrenoceptor agonist, an antiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agent and a urinary alkalinizer, for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease associated with hyperglycemia or a disease associated with the increase of blood galactose level.
 39. A use of (A) a pyrazole derivative claimed in claim 1, a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, a SGLT2 inhibitor, an insulin or insulin analogue, a glucagon receptor antagonist, an insulin receptor kinase stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 analogue, a glucagon-like peptide-1 agonist, amylin, an amylin analogue, an amylin agonist, an aldose reductase inhibitor, an advanced glycation endproducts formation inhibitor, a protein kinase C inhibitor, a γ-aminobutyric acid receptor antagonist, a sodium channel antagonist, a transcript factor NF-KB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth factor analogue, epidermal growth factor, nerve growth factor, a carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrhoics, cathartics, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a β₃-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microsomal triglyceride transfer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a squalene synthase inhibitor, a low-density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihypertensive agent, a sympathetic blocking agent, a centrally acting antihypertensive agent, an α₂-adrenoceptor agonist, an antiplatelets agent, a uric acid synthesis inhibitor, a uricosuric agent and a urinary alkalinizer, for the manufacture of a pharmaceutical composition for the inhibition of advancing impaired glucose tolerance or impaired fasting glycemia into diabetes in a subject.
 40. A pyrazole derivative represented by the general formula:

wherein R¹¹ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a hydroxy(C₂₋₆ alkyl) group which may have a protective group, a C₃₋₇ cycloalkyl group, a C₃₋₇ cycloalkyl-substituted (C₁₋₆ alkyl) group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or an aryl(C₁₋₆ alkyl) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring; one of Q² and T² represents a 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group, a 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy group, a 2,3,4,6-tetra-O-acetyl-p-D-galactopyranosyloxy group or a 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyloxy group, while the other represents a C₁₋₆ alkyl group, a halo(C₁₋₆ alkyl) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkyl) group or a C₃₋₇ cycloalkyl group; R¹² represents a hydrogen atom, a halogen atom, a hydroxy group which may have a protective group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, a halo(C₁₋₆ alkyl) group, a halo(C₁₋₆ alkoxy) group, a C₁₋₆ alkoxy-substituted (C₁₋₆ alkoxy) group, a C₃₋₇ cycloalkyl-substituted (C₂₋₆ alkoxy) group or -A-R^(1A) in which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, —OCH₂— or —CH₂O—; and R^(1A) represents a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group, a halo(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group, a carboxy group which may have a protective group, a C₂₋₇ alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a C₁₋₆ alkyl group; X represents a single bond, an oxygen atom or a sulfur atom; Y¹ represents a C₁₋₆ alkylene group which may be substituted by a hydroxy group which may have a protective group, or a C₂₋₆ alkenylene group; Z¹ represents —R^(1B), —COR^(1C), —SO₂R^(1C), —CON(R^(1D))R^(1E), —SO₂NHR^(1F) or —C(═NR^(1G))N(R^(1H))R^(1I); R^(1C) represents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group which may have a protective group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (ii); R¹⁴, R^(1B), R^(1D), R^(1E) and R^(1F) are the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group which may have a protective group and a C₁₋₆ alkyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (ii), or both of R¹⁴ and R^(1B) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group which may have a protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, or both of R^(1D) and R^(1E) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group which may have a protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group; R^(1G), R^(1H) and R^(1I) are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C₂₋₇ acyl group, a C₂₋₇ alkoxycarbonyl group, an aryl(C₂₋₇ alkoxycarbonyl) group, a nitro group, a C₁₋₆ alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C₁₋₆ alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (ii), or both of R^(1G) and R^(1H) bind to form an ethylene group, or both of R^(1H) and R^(1I) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group which may have a protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group; R³, R⁵ and R⁶ are the same or different, and each represents a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group; and substituent group (ii) consists of a hydroxy group which may have a protective group, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, an amino group which may have a protective group, a mono or di(C₁₋₆ alkyl)amino group which may have a protective group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group which may have a protective group, an ureido group, a sulfamide group, a mono or di(C₁₋₆ alkyl)ureido group, a mono or di(C₁₋₆ alkyl)sulfamide group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkylsulfonyl group, a carboxy group which may have a protective group, a C₂₋₇ alkoxycarbonyl group, —CON(R^(1J))R^(1K) in which R^(1J) and R^(1K) are the same or different, and each represents a hydrogen atom or a C₁₋₆ alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group which may have a protective group, an amino group which may have a protective group, a mono or di(C₁₋₆ alkyl)amino group which may have a protective group, a mono or di[hydroxy(C₁₋₆ alkyl)]amino group which may have a protective group, an ureido group, a mono or di(C₁₋₆ alkyl)ureido group, a C₂₋₇ acylamino group, a C₁₋₆ alkylsulfonylamino group and a carbamoyl group, or both of R^(1J) and R^(1K) bind together with the neighboring nitrogen atom to form a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group which may have a protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, an aryl(C₁₋₆ alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, an aryl(C₁₋₆ alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group on the ring, a C₃₋₇ cycloalkyl group, a C₂₋₆ heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group which may have a protective group, an amino group which may have a protective group, a C₁₋₆ alkylsulfonylamino group, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group which may have a protective group and a C₁₋₆ alkyl group, a C₂₋₆ cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group which may have a protective group, a carbamoyl group, a C₁₋₆ alkyl group, an oxo group, a carbamoyl(C₁₋₆ alkyl) group, a hydroxy(C₁₋₆ alkyl) group which may have a protective group and a C₁₋₆ alkylsulfonylamino-substituted (C₁₋₆ alkyl) group, and a C₁₋₄ aromatic cyclic amino group which may have a C₁₋₆ alkyl group as a substituent, or a salt thereof. 